Immunogenicity and Safety of a Hexavalent DTwP-IPV-HB-PRP~T Vaccine Versus Separate DTwP-HB-PRP~T, bOPV, and IPV Vaccines Administered at 2, 4, 6 Months of Age Concomitantly With Rotavirus and Pneumococcal Conjugate Vaccines in Healthy Infants in Thailand.

BACKGROUND: This study investigated the immunogenicity and safety of a fully liquid, hexavalent, diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)-inactivated poliovirus (IPV)-hepatitis B (HB)- Haemophilus influenzae b (PRP-T) vaccine compared to licensed DTwP-HB-PRP~T, IPV, and bivalent oral poliovirus (bOPV) vaccines following co-administration with other pediatric vaccines [pneumococcal conjugate vaccine (PCV13) and rotavirus vaccine]. METHODS: Phase III, randomized, open-label study in Thailand. Healthy infants received DTwP-IPV-HB-PRP~T at 2, 4 and 6 months of age (N = 228), or DTwP-HB-PRP~T and bOPV (2, 4 and 6 months of age) and IPV (4 months of age) (N = 231). All participants received PCV13 (2, 4 and 6 months of age) and rotavirus vaccine (2 and 4 months of age). Immunogenicity for all antigens was assessed using validated assays, and noninferiority post-third dose was evaluated for anti-D, anti-T, anti-pertussis [anti-pertussis toxin (anti-PT) and anti-fimbriae 2/3 (anti-FIM)], anti-polio 1, 2, 3, anti-HB, and anti-PRP~T. Safety was assessed using parental reports. RESULTS: Noninferiority was demonstrated for each antigen, and overall noninferiority of DTwP-IPV-HB-PRP~T versus DTwP-HB-PRP~T+bOPV+IPV was concluded. Similarity in each group was observed for the GMC ratio for antirotavirus antibodies (20.9 and 17.3, respectively) and anti-PCV13 antibodies (range: 8.46-32.6 and 7.53-33.1, respectively). Two serious adverse events were related to DTwP-IPV-HB-PRP~T (febrile convulsion and acute febrile illness) and 1 was related to DTwP-HB-PRP~T+bOPV+IPV (febrile seizure), but overall there were no safety concerns with similar rates of participants experiencing solicited (99.1% and 98.3%) and unsolicited (19.3% and 19.5%) adverse events in each group. CONCLUSIONS: This study confirmed the suitability of DTwP-IPV-HB-PRP~T primary series vaccination in combination with rotavirus and PCV13 vaccines.

Effects of maternal antibodies in infants on the immunogenicity and safety of inactivated polio vaccine in infants.

The presence of maternal poliovirus antibodies may interfere with the immune response to inactivated polio vaccine (IPV), and its influence on the safety of vaccination is not yet understood. A total of 1146 eligible infants were randomly assigned (1:1) to the IPV and Sabin IPV (SIPV) groups to compare and analyze the efficacy of the two vaccines in preventing poliovirus infection. We pooled the SIPV and IPV groups and reclassified them into the maternal poliovirus antibody-positive group (MAPG; ≥1: 8) and the maternal poliovirus antibody-negative group (MANG; <1: 8). We evaluated the impact of maternal poliovirus antibodies by comparing the geometric mean titer (GMT), seroconversion rate, and geometric mean increase (GMI) of types I-III poliovirus neutralizing antibodies post-vaccination, and incidence rates of adverse reactions following vaccination between the MAPG and MANG. Respective seroconversion rates in the MAPG and MANG were 94% and 100%, 79.27% and 100%, and 93.26% and 100% (all serotypes, P < .01) for types I-III poliovirus, respectively. The GMT of all types of poliovirus antibodies in the MAPG (1319.13, 219.91, 764.11, respectively) were significantly lower than those in the MANG (1584.92, 286.73, 899.59, respectively) (P < .05). The GMI in the MAPG was significantly lower than that in the MANG (P < .05). No statistically significant difference in the incidence of local and systemic adverse reactions was observed between the MAPG and MANG. Thus, the presence of maternal poliovirus antibodies does not affect the safety of IPV but can negatively impact the immune responses in infants after IPV vaccination.

Intradermal administration of fractional doses of the inactivated poliovirus vaccine in a campaign: a pragmatic, open-label, non-inferiority trial in The Gambia.

BACKGROUND: A rapid increase in circulating vaccine-derived poliovirus type 2 outbreaks, and the need to reserve inactivated poliovirus vaccine (IPV) for routine immunisation, has increased the value of fractional dose IPV (fIPV) as a measure to prevent acute flaccid paralysis. However, the intradermal route of administration has been viewed as prohibitive to outbreak response campaigns. We aimed to establish the immunogenicity and safety of administering intradermal fIPV with a disposable syringe jet injector (DSJI) or an intradermal adaptor (IDA) compared with standard administration with a BCG needle and syringe (N&S). METHODS: This pragmatic, non-inferiority trial was undertaken in a campaign setting in communities in The Gambia. Children aged 4-59 months without contraindication to vaccination were eligible. Children were not individually randomly assigned; instead, the vaccination teams were randomly assigned (1:1:1) to one of three administration methods. Parents and the field team were not masked, but laboratory personnel were masked. Baseline demographic and anthropometric data were collected from the participants. Public health officers experienced at intradermal immunisation, and nurses without experience, had 2 h of training on each of the administration methods before the campaign. Participants were vaccinated using the administration method in use by the vaccination team in their community. Poliovirus serum neutralising antibodies (SNA) were measured in children aged 24-59 months before and 4 weeks after vaccination. Adverse events and data on injection quality were collected from all participants. The primary outcome was the type 2 immune response rate (seroconversion in seronegative [SNA titre <8] children plus a 4-fold titre rise in seropositive children). Adjusted differences in the immune response between the DSJI or IDA group versus the N&S group were calculated with 97·5% CIs. A margin of -10% was used to define the non-inferiority of DSJI or IDA compared to N&S. Immunogenicity analysis was done per protocol. The trial is registered with ClinicalTrials.govNCT02967783 and has been completed. FINDINGS: Between Oct 28 and Dec 29, 2016, 3189 children aged 4-59 months were recruited, of whom 3170 were eligible. Over 3 days, 2720 children were vaccinated (N&S, 917; IDA, 874; and DSJI, 929). Among 992 children aged 25-59 months with a baseline SNA available, 90·1% (95% CI 86·1-92·9; 281/312) of those vaccinated using the DSJI had an immune response to type 2 compared with 93·8% (90·6-95·8; 331/353) of those vaccinated with N&S and 96·6% (94·0-98·0; 316/327) of those vaccinated with IDA. All (53/53) type 2 seronegative children seroconverted. For polio type 2, non-inferiority was shown for both the IDA (adjusted difference 0·7% [97·5% CI -3·3 to 4·7], unadjusted difference 2·9% [-0·9 to 6·8]) and DSJI (adjusted difference -3·3% [-8·3 to 1·5], unadjusted difference -3·7% [-8·7 to 1·1]) compared with N&S. Non-inferiority was shown for type 1 and 3 for the IDA and DSJI. Neither injection quality nor the training and experience of the vaccinators had an effect on immune response. No safety concerns were reported. INTERPRETATION: In a campaign, intradermal fIPV is safe and generates consistent immune responses that are not dependent on vaccinator experience or injection quality when administered using an N&S, DSJI, or IDA. Countries facing vaccine-derived poliovirus type 2 outbreaks should consider fIPV campaigns to boost population immunity and prevent cases of acute flaccid paralysis. FUNDING: World Health Organization and the Medical Research Council.

Safety and Immunogenicity of a New Inactivated Polio Vaccine Made From Sabin Strains: A Randomized, Double-Blind, Active-Controlled, Phase 2/3 Seamless Study.

BACKGROUND: A new inactivated polio vaccine made from Sabin strains (sIPV) was developed as part of the global polio eradication initiative. METHODS: This randomized, double-blind, active-controlled, phase 2/3 seamless study was conducted in 2 stages. Healthy infants aged 6 weeks were randomly assigned to receive 3 doses of 1 of 4 study vaccines at 6, 10, and 14 weeks of age (336 received low-, middle-, or high-dose sIPV, or conventional IPV [cIPV] in stage I, and 1086 received lot A, B, or C of the selected sIPV dose, or cIPV in stage II). The primary outcome was the seroconversion rate 4 weeks after the third vaccination. RESULTS: In stage I, low-dose sIPV was selected as the optimal dose. In stage II, consistency among the 3 manufacturing lots of sIPV was demonstrated. The seroconversion rates for Sabin and wild strains of the 3 serotypes after the 3-dose primary series were 95.8% to 99.2% in the lot-combined sIPV group and 94.8% to 100% in the cIPV group, proving the noninferiority of sIPV compared to cIPV. No notable safety risks associated with sIPV were observed. CONCLUSIONS: Low-dose sIPV administered as a 3-dose vaccination was safe and immunogenic compared to cIPV. CLINICAL TRIALS REGISTRATION: NCT03169725.

Fractional dose compared with standard dose inactivated poliovirus vaccine in children: a systematic review and meta-analysis.

BACKGROUND: Since WHO recommended introduction of at least a single dose of inactivated poliovirus vaccine (IPV) in routine immunisation schedules, there have been global IPV shortages. Fractional-dose IPV (fIPV) administration is one of the strategies to ensure IPV availability. We reviewed studies comparing the effects of fractional with full-dose IPV vaccination to determine when seroconversion proportions with each strategy become similar in children aged 5 years and younger. METHOD: In this systematic review and meta-analysis, we searched 16 databases in July, 2019, for trials and observational studies, including ongoing studies that compare immunogenicity and adverse events of fractional-dose (0·1 mL) to full-dose (0·5 mL) IPV in healthy children aged 5 years or younger regardless of study design, number of doses, and route of administration. Screening, selection of articles, data extraction, and risk of bias assessment were done in duplicate, and conflicts were resolved by discussion or arbitration by a third author. We assessed immunogenicity, the main outcome, as proportion of seroconverted participants and changes in geometric mean titres of anti-poliovirus antibodies. Timepoints were eligible for analysis if measurements were done at least 4 weeks after vaccination. Summary estimates were pooled by use of random-effects meta-analysis. Analysis was stratified by study design, type of outcome measure, type of poliovirus, and number of doses given. We assessed heterogeneity using the χ2 test of homogeneity and quantified it using the I2 statistic. We assessed risk of bias using the Cochrane risk of bias tool, and the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. The study is registered with PROSPERO, CRD42018092647. FINDINGS: 860 records were screened for eligibility, of which 36 potentially eligible full-text articles were assessed and 14 articles were included in the final analysis: two ongoing trials and 12 articles reporting on ten completed studies. For poliovirus type 2, there were no significant differences in the proportions of seroconversions between fractional and full doses of IPV for two or three doses: the risk ratio for serconversion at one dose was 0·61 (95% CI 0·51-0·72), at two doses was 0·90 (0·82-1·00), and at three doses was 0·95 (0·91-1·00). Geometric mean titres (GMTs) for poliovirus type 2 were lower for fIPV than for full-dose IPV: -0·51 (95% CI -0·87 to -0·14) at one dose, -0·49 (-0·70 to -0·28) at two doses, and -0·98 (-1·46 to -0·51) at three doses. The seroconversion meta-analysis for the three-dose comparison was homogeneous (p=0·45; I2=0%), whereas heterogeneity was observed in the two-dose (p<0·00001; I2=88%) and one-dose (p=0·0004; I2=74%) comparisons. Heterogeneity was observed in meta-analyses of GMTs for one-dose (p<0·00001; I2=92%), two-dose (p=0·002; I2=80%), and three-dose (p<0·00001; I2=93%) comparisons. Findings for types 1 and 3 were similar to those for type 2. The certainty of the evidence was high for the three-dose comparisons and moderate for the rest of the comparisons. INTERPRETATION: There is no substantial difference in seroconversion between three doses of fIPV and three doses of full-dose IPV, although the full dose gives higher titres of antibodies for poliovirus type 1, 2, and 3. Use of fractional IPV instead of the full dose can stretch supplies and possibly lower the cost of vaccination. FUNDING: South African Medical Research Council and the National Research Foundation of South Africa.

Effect of Haemophilus influenzae Type b Vaccination on Nasopharyngeal Carriage Rate in Children, Tehran, 2019.

BACKGROUND: Haemophilus influenzae (H. influenzae) strains, which commonly reside as commensals within the human pharynx and can remain as an asymptomatic carrier, but become invasive leading to pneumonia, septic arthritis, or meningitis. The Pentavac (pentavalent vaccine, manufactured by India, SII (DTwP-HepB-Hib)) was introduced to the Iranian National Immunization Plan in November 2014. The aim of this study is to investigate H. influenzae type b (Hib) carrier rate among children under 6 years old in Tehran. METHODS: This cross-sectional study was performed on 902 children including vaccinated/unvaccinated in the age of 6 months to 6 years, in Tehran. Sampling was performed from July 2019 to September 2019. Nasopharyngeal samples were taken from children by sterile swab. The PCR method was used to extract DNA. Then, all H. influenzae isolates were initially confirmed by molecular tests. BexA was used to distinguish typeable H. influenzae strains from nontypeable Haemophilus influenzae (NTHi). RESULTS: A total of 902 children were enrolled in the study: 452 were female (51%). H. influenzae carriage rate was 267 (29%), of that 150 samples (16.6%) were typeable. The nasopharyngeal Hib carrier rate in the children was 2.6% (24/902). 262 cases did not receive Hib vaccine. Analysis in nonnursery's children aged 4 to 6 (unvaccinated) years showed that the lower educational level of father, mother, and family number correlated with increased odds of colonization of children with Hib. CONCLUSION: Our findings showed a significant decrease (60%) in the overall Hib nasopharyngeal carriage in healthy children under six years after 5 years after the start of Hib vaccination.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine administered concomitantly with other paediatric vaccines in toddlers: a phase III randomised study.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Implication of a High Risk for Type 2 Vaccine-Derived Poliovirus Emergence and Transmission After the Switch From Trivalent to Bivalent Oral Poliovirus Vaccine.

BACKGROUND: China implemented the globally synchronized switch from trivalent oral poliovirus vaccine (tOPV) to bivalent OPV (bOPV) and introduced 1 dose of inactivated poliovirus vaccine on 1 May 2016. We assessed the impact of the switch on the immunity level against poliovirus, especially type 2. METHODS: Children born between 2014 and 2017, who were brought to the hospitals in Urumqi city, Xinjiang Province in 2017, were enrolled and blood samples were collected to test for antibody titers against poliovirus. A comparison of seroprevalence between the children born before (preswitch group) and after the switch (postswitch group) was performed to assess the impact of the switch on the immunity level against polio. RESULTS: A total of 172 subjects were enrolled. The overall seroprevalences were 98.8%, 79.1%, and 98.3% for types 1, 2, and 3, respectively. Seroprevalence for type 2 significantly decreased from 91.6% in the preswitch group to 67.4% in the postswitch group, but no statistically significant change was observed for both types 1 and 3. CONCLUSIONS: The switch from tOPV to bOPV can provide high-level immunity against types 1 and 3 but not against type 2, indicating a high risk of type 2 vaccine-derived poliovirus emergence and transmission.

Safety and immunogenicity of inactivated poliovirus vaccine schedules for the post-eradication era: a randomised open-label, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule. METHODS: This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama and one in the Dominican Republic. Eligible participants were healthy 6-week-old infants with no signs of febrile illness or known allergy to vaccine components. Infants were randomly assigned (1:1:1:1, 1:1:1:2, 2:1:1:1), using computer-generated blocks of four or five until the groups were full, to one of four groups and received: two doses of intradermal f-IPV (administered at 14 and 36 weeks; two f-IPV group); or three doses of intradermal f-IPV (administered at 10, 14, and 36 weeks; three f-IPV group); or two doses of intramuscular IPV (administered at 14 and 36 weeks; two IPV group); or three doses of intramuscular IPV (administered at 10, 14, and 36 weeks; three IPV group). The primary outcome was seroconversion rates based on neutralising antibodies for poliovirus type 1 and type 2 at baseline and at 40 weeks (4 weeks after the second or third vaccinations) in the per-protocol population to allow non-inferiority and eventually superiority comparisons between vaccines and regimens. Three co-primary outcomes concerning poliovirus types 1 and 2 were to determine if seroconversion rates at 40 weeks of age after a two-dose regimen (administered at weeks 14 and 36) of intradermally administered f-IPV were non-inferior to a corresponding two-dose regimen of intramuscular IPV; if seroconversion rates at 40 weeks of age after a two-dose IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose IPV regimen (weeks 10, 14, and 36); and if seroconversion rates after a two-dose f-IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose f-IPV regimen (weeks 10, 14, and 36). The non-inferiority boundary was set at -10% for the lower bound of the two-sided 95% CI for the seroconversion rate difference.. Safety was assessed as serious adverse events and important medical events. This study is registered on ClinicalTrials.gov, NCT03239496. FINDINGS: From Oct 23, 2017, to Nov 13, 2018, we enrolled 773 infants (372 [48%] girls) in Panama and the Dominican Republic (two f-IPV group n=217, three f-IPV group n=178, two IPV group n=178, and three IPV group n=200). 686 infants received all scheduled vaccine doses and were included in the per-protocol analysis. We observed non-inferiority for poliovirus type 1 seroconversion rate at 40 weeks for the two f-IPV dose schedule (95·9% [95% CI 92·0-98·2]) versus the two IPV dose schedule (98·7% [95·4-99·8]), and for the three f-IPV dose schedule (98·8% [95·6-99·8]) versus the three IPV dose schedule (100% [97·9-100]). Similarly, poliovirus type 2 seroconversion rate at 40 weeks for the two f-IPV dose schedule (97·9% [94·8-99·4]) versus the two IPV dose schedule (99·4% [96·4-100]), and for the three f-IPV dose schedule (100% [97·7-100]) versus the three IPV dose schedule (100% [97·9-100]) were non-inferior. Seroconversion rate for the two f-IPV regimen was statistically superior 4 weeks after the last vaccine dose in the 14 and 36 week schedule (95·9% [92·0-98·2]) compared with the 10 and 14 week schedule (83·2% [76·5-88·6]; p=0·0062) for poliovirus type 1. Statistical superiority of the 14 and 36 week schedule was also found for poliovirus type 2 (14 and 36 week schedule 97·9% [94·8-99·4] vs 10 and 14 week schedule 83·9% [77·2-89·2]; p=0·0062), and poliovirus type 3 (14 and 36 week schedule 84·5% [78·7-89·3] vs 10 and 14 week schedule 73·3% [65·8-79·9]; p=0·0062). For IPV, a two dose regimen administered at 14 and 36 weeks (99·4% [96·4-100]) was superior a 10 and 14 week schedule (88·9% [83·4-93·1]; p<0·0001) for poliovirus type 2, but not for type 1 (14 and 36 week schedule 98·7% [95·4-99·8] vs 10 and 14 week schedule 95·6% [91·4-98·1]), or type 3 (14 and 36 week schedule 97·4% [93·5-99·3] vs 10 and 14 week schedule 93·9% [89·3-96·9]). There were no related serious adverse events or important medical events reported in any group showing safety was unaffected by administration route or schedule. INTERPRETATION: Our observations suggest that adequate immunity against poliovirus type 1 and type 2 is provided by two doses of either IPV or f-IPV at 14 and 36 weeks of age, and broad immunity is provided with three doses of f-IPV, enabling substantial savings in cost and supply. These novel clinical data will inform global polio immunisation policy for the post-eradication era. FUNDING: Bill & Melinda Gates Foundation.

Persistence of Hepatitis B Immune Memory Until 6 Years of Age Following Hexavalent DTaP-IPV-HB-PRP~T Vaccination in a 3-, 5- and 11- to 12-month Schedule and Response to a Subsequent Hepatitis B Challenge Vaccination.

Anti-hepatitis B (HBs) antibody persistence and hepatitis B challenge were evaluated at 6 years of age following vaccination of fully liquid DTaP-IPV-HB-PRP~T or reconstituted DTaP-IPV-HB//PRP~T at 3, 5, 11-12 months of age. At 6 years, 53.8% and 73.5% had seroprotective anti-HBs antibodies (≥10 mIU/mL), increasing to 96.7% and 95.9% postchallenge, confirming a strong anamnestic response in primed vaccinees.

Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.

BACKGROUND: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants. METHODS: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798. FINDINGS: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity. INTERPRETATION: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation. FUNDING: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation.

Safety and immunogenicity of co-administration of meningococcal type A and measles-rubella vaccines with typhoid conjugate vaccine in children aged 15-23 months in Burkina Faso.

OBJECTIVES: The World Health Organization pre-qualified single-dose typhoid conjugate vaccine (TCV) and requested data on co-administration with routine vaccines. The co-administration of Typbar TCV (Bharat Biotech International) with routine group A meningococcal conjugate vaccine (MCV-A) and measles-rubella (MR) vaccine was tested. METHODS: This was a double-blind, randomized controlled trial performed in Ouagadougou, Burkina Faso. Children were recruited at the 15-month vaccination visit and were assigned randomly (1:1:1) to three groups. Group 1 children received TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; group 2 children received TCV and MCV-A; group 3 children received MCV-A and control vaccine. Routine MR vaccine was administered to all participants. Safety was assessed at 0, 3, and 7 days after immunization, and unsolicited adverse events and serious adverse events were assessed for 28 days and 6 months after immunization, respectively. RESULTS: A total of 150 children were recruited and vaccinated. Solicited symptoms were infrequent and similar for TCV and control recipients, as were adverse events (group 1, 61.2%; group 2, 64.0%; group 3, 68.6%) and serious adverse events (group 1, 2.0%; group 2, 8.0%; group 3, 5.9%). TCV generated robust immunity without interference with MCV-A vaccine. CONCLUSIONS: TCV can be safely co-administered at 15 months with MCV-A without interference. This novel study on the co-administration of TCV with MCV-A provides data to support large-scale uptake in sub-Saharan Africa.

One-Year Decline of Poliovirus Antibodies Following Fractional-Dose Inactivated Poliovirus Vaccine.

BACKGROUND: Fractional dose (one-fifth of full intramuscular dose) of inactivated poliovirus vaccine (fIPV) administered intradermally is used as IPV dose-sparing strategy. We compared the rate of decline of poliovirus antibodies (PVA) in recipients of 2 doses of fIPV or IPV. METHODS: A community-based randomized controlled trial was conducted in Karachi, Pakistan. Children aged 14 weeks were randomized into fIPV or full IPV (study arms A, B) and received 1 vaccine dose at age 14 weeks and 1 at age 9 months. PVAs were measured at age 14, 18 weeks and 10, 21 months. RESULTS: Seroprevalence of poliovirus type 2 antibodies in 170/250 (68%) children after 2 IPV or fIPV doses at age 10 months in A and B reached 100% vs 99% (P = .339), and at 21 months, 86% vs 67% (P = .004). Between age 10 and 21 months antibody log2 titers dropped from ≥ 10.5 to 6.8 in A and from 9.2 to 3.7 in B. CONCLUSIONS: There was a significant decline in antibody titers 12 months following the second IPV dose. The slope of decline was similar for full IPV and fIPV recipients. The results provide further evidence that fIPV is a viable option for IPV dose-sparing. CLINICAL TRIALS REGISTRATION: NCT03286803.

Media briefing on COVID-19 - 06/11/2020

00:00:15 FC Hello, everybody. I am Fadela Chaib, speaking to you from WHO headquarters in Geneva and welcoming you to our global COVID-19 press conference today, Friday 6th November. We have the privilege of welcoming three Health Ministers from Indonesia, South Africa and Thailand. Unfortunately the Minister of Uzbekistan is no longer able to join us as planned. The Health Ministers will share their countries' experiences on preparedness and the response to COVID-19. I will let Dr Tedros introduce Their Excellencies. The Director-General, Dr Tedros, will be joining us remotely. Present in the room are Dr Mike Ryan, Executive Director, Health Emergencies, Dr Maria Van Kerkhove, Technical Lead for COVID-19, Dr Stella Chungong, Director, Health Security Preparedness, Dr Jaouad Mahjour, Assistant Director-General, Emergency Preparedness, Mr Steve Solomon, Principal Legal Officer. In the room also are Dr Soumya Swaminathan, Chief Scientist, Dr Mariangela Simao, Assistant Director-General, Access to Medicines and Health Products. Welcome, all. Simultaneous interpretation is provided in the six official UN languages plus Portuguese and Hindi. Now without further ado I will hand over to our Director-General, Dr Tedros, for his opening remarks and for him to introduce our guests. Dr Tedros, you have the floor. 00:02:03 I think you are muted, Dr Tedros. TAG [Inaudible]. FC Dr Tedros, can you hear me? You are muted, Dr Tedros. TAG Can you hear me now? FC Good. Go ahead, please. TAG I think there is a few minutes' lapse, pause time. Good morning, good afternoon and good evening. In the summer Africa was certified as wild polio free. This marked one of the greatest public health achievements of all time, driven by millions of health workers reaching every child repeatedly with an effective vaccine and a unique partnership between WHO, UNICEF, Rotary, CDC, the Bill and Melinda Gates Foundation and GAVI. Global polio eradication remains achievable. However the COVID-19 pandemic hurt momentum as polio and immunisation efforts were suspended. This left children, especially in high-risk areas, more vulnerable to killer diseases like polio, measles and pneumonia and now we are starting to see outbreaks of these diseases. 00:04:13 We need to turn the tide quickly and ensure no child is left behind. Today WHO and UNICEF are jointly launching an emergency appeal to rapidly boost measles and polio vaccination. While the world watches intently as scientists work to ensure safe and effective vaccines are developed for COVID-19 it's important to ensure that all children receive the life-saving vaccines that are already available. We estimate that US$655 million is needed to address dangerous immunisation gaps in children in non-GAVI-elegible countries. This is a global call to action for all donors to stay the course and not to turn their backs on the poorest and most marginalised children in their hour of need. While the COVID-19 pandemic continues to evolve we must take all opportunities to learn and improve the response as we go. Many countries heard our call back in January when we rang our highest alarm by calling a Public Health Emergency of International Concern. They worked closely with us and followed the parameters set out in the strategic response plan that WHO outlined on 4th February. They have conducted reviews, shared data and experience and honed their response to their national experience and unique situation on the ground. 00:06:00 As the pandemic unfolds, as countries have reflected they have used intra-action reviews to make their responses stronger. This kind of self-analysis review is what the world called for during the World Health Assembly back in May. An intra-action review uses a whole-of-society, multisectoral approach, acknowledging the contributions of all relevant stakeholders involved in COVID-19 preparedness and response at the national and subnational levels. By reviewing and adopting the current preparedness and response strategies and identifying what's working well and what needs to be strengthened the review gives countries the opportunity to change the trajectory of the pandemic. intra-action reviews not only help countries improve their COVID-10 response but also contribute towards their long-term health security. To date 21 countries have completed them and others are in the pipeline. Today we're happy to welcome the Ministers of Health from Indonesia, the Kingdom of Thailand and South Africa to share their experience and lessons from COVID-19. 00:07:24 I would like to first introduce His Excellency, the Deputy Prime Minister and Minister of Health of the Kingdom of Thailand, Minister/Deputy Prime Minister Anutin Charnvirakul. The floor is yours, Your Excellency. AC Dr Tedros, Director-General of the World Health Organization, Health Ministers, colleagues, members of the press, I send you greetings from Thailand. As you know, Thailand was the first country outside of China to detect a case of COVID-19 and since then we have been working around the clock to prevent the spread of the disease. Several strategies are employed such as comprehensive case identification, rigorous contact tracing and quarantine. Thai people are well complying with the social measures of wearing masks, hand hygiene and physical distancing, resulting in the effective control of the spread of COVID-19 in our country. We have maintained zero local transmission for many months. Nowadays few cases were detected in the quarantine area. We are well aware of the need to continuously improve response to COVID-19 to protect the health of all people across the globe, including Thailand. 00:09:12 So the joint intra-action review of Thailand's response to COVID-19 was critical. It was conducted during July 20th to July 24th by 16 reviewers from diverse backgrounds, rating the experts from WHO, UN agencies, USCDC and two academies [?]. I thank the review panel who interviewed 96 Thai policymakers, technical experts and respondents and all relevant persons who contributed to this review. The reviewers made their observations and recommendations based on consensus. They highlighted the factors that helped Thailand successfully control the spread of COVID-19 so far. Those include decisive leadership based on the best scientific evidence available, our strong public health system and the strong whole-of-society approach across sectors, cooperation and collaboration with our concerned sectors among the public and private sectors, civil society and many institutions played important roles in breaking the chains of transmission. 00:10:45 My highest appreciation is going to everyone in Thailand for their collective effort in curtailing the outbreak in our country. Besides our strengths the review identifies the challenges for further improvement. First is to integrate information around COVID-19 and maximise its benefit. Second is to expand our surveillance systems by improving capacity to detect cases and increasing the efficiency of our emergency operations centres. Third is to advance the integrated digital data system for managing the situation and ensuring health security for everyone on Thai soil. Distinguished colleagues, IR report reminds us the strengths that we need to maintain. At the same time it advises us the challenges we need to address. We commit to improving our response to COVID-19 by working closely with relevant stakeholders. In this regard I would like to thank all of our partners who have worked with us on the report including WHO, various UN agencies, US CDC and national colleagues in the academic sector. My special thanks goes to my colleagues at the Ministry of Public Health and our health workers who provide services across Thailand. 00:12:30 Finally I appreciate the role of the media in disseminating and advocating news and information that helps us communicate with the public more effectively to prevent the spread of the disease. Only together can we win the COVID-19 pandemic and we shall win. Thank you very much. Kob kun kap. TAG Sa wadi kap. AC Kob kun kap. TAG Thank you so much, Deputy Prime Minister, for those insightful remarks and lessons regarding Thailand's response. I would now like to welcome His Excellency, Minister of Health, South Africa, Dr Zwele Mkhize. Your Excellency, the floor is yours. ZM Thank you very much, Director-General, my brother, Dr Tedros, Honourable Ministers, representatives from various countries in the Department of Health and members of the media and the public. 00:13:44 I'd like someone to help me share the slides from your side if that is possible. Thank you very much. I'd like to just take a quick walk through our journey on COVID-19 and therefore I'd like to go to the next slide. The presentation is going to give us a quick overview and then why are we going through our intra-action review, what lessons we have learnt and the way forward. Next slide, please. This gives us a sense of the journey of the South African fight against COVID. All the red lines there indicate how we've moved under heavy lock-down and it went downwards in a risk-adjusted way until we got to level three and then of course you'll see that that's when the surge started, early in June and then up to July when we had 13,000 positive tests per day and then they started declining and thereafter when it was to plateau we went to the next level of the lock-down. We've continued on a plateau now and in this part we've even started opening up international travel. Next slide. At this point we've got 1,500 to 2,000 daily new positive cases, 732,000 cumulative cases, 91% recovery and 2.7% fatality rate and and 41,000 active cases. Thank you, next slide. 00:15:24 This is the toolkit. I think all of us have used this, from governors to case management to tracing to tracking to information to human resources and all the issues that we're going to employ. Next slide. Through this interacting review and on our own re-evaluation going back we've learnt a lot of lessons. Firstly there the issues of national co-ordination, leadership and governance with various structures become important. Evidence-based response is important to ensure that science leads everything. The strengthening of emergency procurement processes to mitigate against corruption. Strong primary healthcare is important. Issues of fatigue must be given attention too. Close collaboration with labour and other social partners. Public/private partnership is important. Harnessing of power of technology, digital contact tracing is also important and information dissemination and then issues of continued vigilance and aggressive response to cluster outbreaks. Continued assessment of capacity of projected multisectoral and multifactorial impact. 00:16:37 It's important to know that we need everybody to be touched by our response on this matter. The economic impact is a major issue. The country and the citizens and the poor have to be protected and the impact of non-COVID health services is also something that we have to take into account. Next slide. This is how, as we observe at subnational level, we've still kept the plateau but there are indications of clusters breaking up and showing a slight increase in some of the areas and so we're watching over that and that's why the intra-action review becomes important. Next slide. The concerns that we have to take into account at this point, which is why we're focused on this intra-action review. There is pandemic fatigue in the population with low adherence to public health measures. Exhaustion and fatigue in the front-line workers, who we must thank for all the work that they've taken on in fighting this COVID-19 even if they themselves became victims, ensuring that they're well protected, well trained and well motivated. Then of course we have to take into account the possible resurgence that can be made worse by the factors above and also the delay in the vaccine still keeps us vulnerable and then of course resources which are dwindling and we're going to move resources from other functions of government to actually help to fight the pandemic. So these are some of the issues that we're now taking into account. Next slide. 00:18:15 In our case we are very grateful for the support of our international partners, led by the WHO using the WHO methodology. We volunteered to work on this and we've gone right to involved. Already eight of the nine provinces have conduced their intra-action review and then we've got a team of 35 WHO SAGE personnel who have come in to reinforce our technical experts on the ground. Next slide. Of the lessons that I've indicated we learnt before, amongst the issues we have looked at are that the value-add of the intra-action review is that it shows us best practice, it enables us to be able to record these and put them across all pillars and then institutionalise them. It also helps us to identify gaps in this case to ensure that our next response is actually seamless. The next is the revision of the response plans. We have plans which are now localised at the lowest local level in districts so that everyone is able to respond without waiting for the additional response but they must know what they need to do. 00:19:30 Then of course there are long-term recommendations that have been put in place and then we're looking at this with continuous follow-ups so it's a whole cycle now of response, intra-action review, resurgence readiness and of course response and that continues. This is now what we're preparing for and we believe the support of WHO has been very helpful to make us ready psychologically to face whatever comes as the next resurgence possible comes up. Next slide. Here learning from other countries that are experienced in COVID resurgence; measures have been taken to prepare for, detect and promptly respond to the resurgence. There is an national plan now of action to mitigate the COVID-19 resurgence which has been developed. Provinces are currently developing their resurgence mitigation plans. These incorporate early-warning systems, as I was saying, broken down right to the district level and all the provinces now are remaining on high alert. 00:20:28 So every day as we watch we look at where the clusters are breaking up; we've seen in the western part of the country and the eastern part of the country and all of these are indicating our state of alertness and this is now based on the WHO resurgence plan. Next slide. Here we've got a quick indicator. Everyone has to look out for anything that's less than a 10% increase or decrease; it's under control. Between ten and 20 it puts us on alert. Now we're looking out for over a 20% increase. That's indicating resurgence and these are some of the key lessons that we've got from our intra-action review and the plans that we have developed together with the WHO as our partners. Next slide. Basically our recommendation is that intra-action reviews are variable exercises that enable countries to recalibrate their responses and in this case in South Africa it has really benefited us greatly and the intra-action review provides [unclear] for adjusting the system and plans for readiness for a potential resurgence and the issue of continuous engagement with all the communities and partners at local and international level ensures that we are able to strengthen our non-pharmaceutical interventions such as social distancing, wearing of masks, hand and respiratory hygiene. You need a community to respond at that level. 00:22:04 Lastly COVID-19 is still with us and therefore we need to remain vigilant, to continue to fight together. We are quite clear that it needs and all-community, all-government and everybody's participation to fight and the strength of the interaction reviews is to actually revive that understanding among all of us so that as we move on we are actually better prepared to respond. Thank you very much for continuing to share the ideas. Thank you very much. TAG Thank you so much, Minister Mkhize; thank you so much for sharing South Africa's determined efforts to tackled COVID-19. I would now like to turn to the Minister of Health of Indonesia, Dr Terawan Agus Putranto. Minister Putranto, the floor is yours. TAP Dr Tedros, Director-General of the World Health Organization; my fellow colleagues, Ministers of Health of Thailand and South Africa, ladies and gentlemen, good morning, afternoon and evening. 00:23:39 It is a pleasure to be invited and participate in today's event. The Ministry of Health of the Republic of Indonesia, supported by WHO's Indonesia country office has conducted a national intra-action review for the COVID-19 response on 11th until 14th August 2020. The IER is an immediate follow-up of the fourth IHR COVID-19 emergency committee meeting recommendation that was held in July 2020. Surely it is not an easy task to bring representatives of 138 multisectoral stakeholders to conduct a review of the existing COVID-19 response activities in Indonesia. However under the leadership of President Joko Widodo and the co-ordination of the COVID-19 Task Force Chief, General Muhot Pinsarpanjiatan [?], Representative from the Technical Unit within the Ministry of Health, of the related Ministries and Government agencies, the national and regional COVID-19 taskforce, military and police forces, provincial and district government, hospital and primary health service facilities, laboratories, universities, professional associations, state-owned enterprises and international organisations have been committed and have been actively involved and contributed [?] to the full process of the IAR. The involvement of the multi-sectoral stakeholders in the review is imperative in gaining a multi-perspective view of the COVID-19 response in Indonesia. This is particularly important because the IAR in Indonesia covers the nine key pillars of the COVID-19 response which consists of the pillar of, one, command and co-ordination. Second, risk communication and community empowerment. Three, surveillance, rapid response team and case investigation. Four, point of entry, international travel and transport. Five, laboratory. Six, infection control. Seven, case management. Eight, operational and logistic support. Nine, maintaining essential health services and systems. In there active participation of such multi stakeholders is a key for the success of IER. Equally important, the multi-sectoral involvement in the IER has also increased the acceptability of the IER recommendations by our stakeholders. As a result the IER recommendations have been used in the revised COVID-19 health sector operational plan at the national and subnational level as well as in updating the COVID-19 partner platform. 00:27:30 IER recommendations contribute to the improvement of the multisectoral stakeholder command and co-ordination at the national and subnational level and also strengthened the periodic monitoring of response plan indicators including surveillance and laboratory co-ordination as well as improved contact tracing, testing and triage at health facilities to avoid exposure of patients and the health workforce to COVID-19. Enforcing the implementation and monitoring of [unclear] social restrictions and empowering the community as [unclear] through COVID-19 key messaging and engagement were also considered as one of the areas for improvement. Furthermore the IER suggested improving telemedicine to prevent COVID-19 exposure and maintain essential health services such as immunisation, tuberculosis, HIV and non-communicable diseases programmes as part of ensuring the continuity of essential health services. 00:29:03 Indonesia will also include the IER result as a reference for the ISR state party annual reporting in the 74WXE. Ladies and gentlemen, Indonesia is of the few that are reviewing the operational plan of COVID-19 response through the multi-sector stakeholder intra-action review as one of the best practices to look collectively, identify best practice, [unclear] and contributing factors for corrective action in the COVID-19 response effort. From our point of view the result of the IER review has provided input for Indonesia to improve multisectoral preparedness co-ordination in line with the multi-sectoral preparedness coordination framework that was published by WHO in May 2020 to strengthen co-ordination for a better health emergency preparedness. Thank you. Terima kasih banyak. TAG Thank you. Thank you so much, Your Excellency. Tirima kasih [inaudible]. FC Hi. We are trying to connect with Dr Tedros so I hope it will be solved very shortly and quickly. Dr Tedros, we lost you but we are trying to fix the problem. We are trying to connect again with Dr Tedros but whilst we are trying to fix this I would like to remind journalists to raise their hands if they want to ask a question, to get in the queue. I would also like to ask them to unmute. Dr Tedros is back, I was told. Dr Tedros, are you with us? Dr Tedros? 00:32:07 Dr Tedros, can you hear me? I cannot hear you. TAG Can you hear me? FC Yes, very well, DG. Go ahead, please. TAG I think after the interruption it needs 30 seconds to unmute. That's the configuration so I was hearing your voice but not mine. I was saying tirima kasih to His Excellency, Minister Putranto, for sharing Indonesia's efforts to suppress COVID-19. Your Excellency, terima kasih again. By conducting reviews in real time and sharing lessons to the world the three countries have reflected a blueprint for how countries can suppress COVID-19 and break the chains of transmission. You can do exercises, you can do simulations but the best time to look at your emergency response capacity is when an emergency is happening. 00:33:32 That's when you can clearly see what works, what doesn't and what you need to improve. There is hope and now is the time to double down on efforts to tackle this virus. Wherever a country is in terms of the outbreak countries can turn it around by driving a whole-of-government and whole-of-society response. It's never too late. While we invest and test vaccines to prove they are safe and effective I'd encourage all countries to learn from Thailand, South Africa and Indonesia and work to suppress this virus today with the tools in hand that we know work. We can save lives and livelihoods and end this pandemic together. I thank you. Back to you, Fadela. FC Thank you, Dr Tedros, and our distinguished guests. I will now open the floor to questions from members of the media. I remind you that you need to raise your hand by using the raise your hand function in order to get in the queue and please make sure you are unmuted. Please, I'm reminding journalists to ask only one question. We will start the question-and-answer session with Stephen Howard from Travel News Asia. Stephen, can you hear me? Stephen? Stephen, can you hear me? 00:35:22 ST Yes. Hello. Can you hear me? FC Yes, hello. You can ask your question. Please go ahead. ST Hello and thank you for taking my question and thank you for all the work that the WHO does. My question is for Kudun Anutin. Thailand is currently looking at reducing the quarantine from 14 days to ten days. I would like to ask please, what is the research behind this, when do you expect that to happen and what are your thoughts on such a reduction, please? Thank you. FC Thank you, Howard. Mr Charnvirakul, do you want to answer this question, Minister of Thailand? No. We are trying to contact again the Honourable Minister of Thailand. In the meantime Dr Van Kerkhove can try to answer this question. Go ahead. MK Thanks. While we try to get them back, there have been some questions about the quarantine period. This is the time in which a contact of a confirmed case needs to be separated from other individuals. We call that quarantine and WHO's recommendation on this is based on what we know the incubation period to be, which is the time from exposure to the time someone develops symptoms. 00:37:07 Our guidance for incubation period is 14 days and that's based on the amount of time that most individuals, 95% of individuals will develop symptoms after exposure. So what we've outlined is this 14-day period and there are some countries that are discussing the possibility of reducing that time period based not a number of factors associated with their response and the capacity to provide supported quarantine. What we understand from a number of countries is that if they do reduce that 14-day period they're considering adding testing as part of that but there is a balance approach that if there is a reduction in that 14-day period there are some risks that are associated with that in terms of missing the potential cases onward. So what we have is our outline based on the science and based on what is understood to be that incubation period. That's where that 14 days comes from. 00:38:04 FC Thank you. The next question is from Kate Killen. Kate, can you hear me? KA Hi. Can you hear me? FC Very well. Go ahead, please. KA Thank you for taking my question. I'm interested in what's happening with mink farms in various parts of the world. We've had a major cull in Denmark announced this week and I wonder, is the WHO advising other countries that have mink farms whether they need to do similar things, close them or cull their herds? Are you also worried that this spread to livestock might happen with other types of livestock and with mutations happening and then coming back into the human population? MK Thanks for this question. I will begin but we also have Dr Peter Vandermerck on the line who's our animal/human interface focal point so I would like to ask him to supplement this answer here. Yes, I'm sure you've seen the reports of the circulation of the SARS-CoV2 virus in minks. We've been seeing this for a number of months now and what we understand is the minks have been infected by contact from humans, it circulates in the mink and then it can pass back to humans. 00:39:33 So there's always a concern when you have circulation and transmission from human to animals and then animals to humans. There are a number of activities that are ongoing to understand the situation in Denmark. We had a very good call with our colleagues in the European regional office and ECDC And also the State Serum Institute in Denmark and this is the group that is evaluating the strains that are being identified in these mink. So the findings that they've found; they've seen some variance in some of these strains that have some mutations and I'd like to remind you that mutations are normal. These types of changes in the virus are something that we have been tracking since the beginning and you've heard me say many times that WHO has a global laboratory network and we have a specific working group that is looking at virus evolution and looking at these changes. Each one of these changes, each one of these mutations, whether they're identified in mink or they're identified in humans, needs to be evaluated because we need to determine the importance of each of these and if any of these changes means that the virus behaves differently. 00:40:42 There's a proper way to do that because there need to be studies to evaluate if there're any changes in transmissibility or severity and if there are any implications for diagnostics, for vaccines and for therapeutics. In this situation there's a suggestion that some of these mutations may have some implications but we need to do the proper studies to evaluate this and that is ongoing right now with colleagues at SSI in Denmark as well as our international working group. We are working with our regional offices in Europe and WPRO in the Western Pacific and in the Americas, where there are mink farms because there are many mink farms all over the globe, and looking at the biosecurity on these mink farms, looking at the surveillance that's happening in these mink farms and to support the countries in taking the right steps to prevent the virus continuing to circulate in minks and to prevent spill-over events from happening. 00:41:38 So the immediate steps that are taken in Denmark are to limit further spill-over of the virus and then making sure that these minks are culled and Denmark has made some announcement on how they are going to do that but I'd like to ask Peter if he could supplement this by talking about how we work with FAO and OIE and our partners in support of this. FC Thank you. Dr Peter Bennemburg, are you online? Peter? PB Yes. FC Please go ahead. PB Thank you. Yes, we are of course working closely with our colleagues in FAO and OIE who have more areas of expertise and speciality around the different animal species and the way they are bred and the risk associated with that. It's clear that with mink different countries have different farming traditions and in some countries the farms are easier to protect in terms of biosecurity measures and so on than in other countries and that explained partly why some countries have been able to control outbreaks in their mink population while other countries have had difficulties doing that. 00:42:58 To the second part of your question about the risk of seeing something happening in a similar way in other animal species, food animal species in particular, there the risk is much less for two reasons. One is that the first studies that have been conducted on pigs, chicken, cattle and so on show that these species are not at all susceptible in the same way that mink are for example so even if these animals were infected they would not be able to sustain and spread the disease in the same way. The second reason is that the way we produce pigs and chickens in particular in modern farming systems allows us to keep these environments totally isolated and secured from a contamination point of view so it will be much easier to contain and prevent the disease coming into these environments if these patients were also susceptible to the virus. Thank you. MR Thank you, Peter. I would echo your words there on biosecurity. Animals are farmed for all kinds of different reasons and it is really important when they're farmed en masse that we have adequate biosafety, adequate risk management measures. 00:44:30 This is an issue all over the world and it's something we continually speak about. The animal/human interface is very dynamic and even with having testing and having awareness of SARS-CoV2 it's taken time to establish how widespread this virus has been in the mink population and then human-to-mink and mink-to-human transmission. It just shows how complex and how dynamic this interface is and how complex some of the answers are when you try to work out the significance of any one of these events. I think that is what the teams are working together on, scientists all over the world on the epi side, on the clinical side, on the laboratory side are working together with our Danish colleagues to establish those facts. We have briefed and worked very closely with our colleagues at the European regional office, with our regional director, Dr Hans Kluge. We've also been in close contact with the European Centre for Disease Control. I know that these data are being sent around in the European Early Warning Response System and I know the European Union is acting... ECDC is the surveillance centre for the European Union and I know the Danish colleagues are also reaching out across Europe themselves. 00:45:50 So there's a lot of very good work and coordination ongoing and WHO; we're just in the process of completing a first risk assessment on this specific event and we will be communicating with our member states in the coming hours today - thank you, Maria - in order to summarise the situation for all of our member states and any ongoing risks. We'd like to thank everybody from the country to the regional to the global level who are working with us. This is the work of science to establish the facts, to assess the risks, to manage those risks and do that in a flexible, rapid and dynamic way. FC Thank you, Dr Ryan. I would like now to pass the floor to Jamie Keaton from Associated Press. Jamie, can you hear me? JA Good morning. Thank you so much, Fadela. There are so many questions to ask right now but there is one that's really pressing and I hope that Dr Tedros can address it. As you may be paying attention to, the United States is in the midst of an election and President Joe Biden or potentially President Joe Biden's administration we may see. 00:47:04 I'm just wondering how much contact you've had with Joe Biden's team and what kind of word have you had about how quickly Joe Biden's administration would bring the United States back into the fold of the WHO. Thank you. MR Steve Solomon will comment on any specifics. We would just like to congratulate all Americans for exercising the wonderful act of democracy that's ongoing there right now and we assure you that the World Health Organization as a member state organisation will continue to work with the US administration and will work with all US administrations now and into the future. Steve. SS Thanks, Mike. I can only reiterate that the Secretariat, based on principles of neutrality, works with all administrations. We will continue to work with the administrations in all of our member states and do so cooperatively and in accordance with the principles set down in the constitution and any decisions that the World Health Assembly adopts in that regard. Thank you. FC Thank you. I would like now to invite Adela Suleiman from NBC to ask the next question. Adela, can you hear me? 00:48:36 AD Hi, yes. Just going back to the [inaudible] question, [inaudible] you're staying on top of it but how worried should everyday people be and secondly will this dash any prospect of a [inaudible] vaccine? MR Soumya may wish to comment on the specifics regarding vaccines. No, I think it's very important to recognise that these types of things happen all the time. This is a global pandemic and many millions of people are infected and many millions of animals have been exposed and we've seen different types of animals who've been themselves infected with this virus. There's always a potential that the virus can then come back to humans and that is a concern because mammal species like mink are very good hosts in a sense and the virus can evolve within those species especially if large numbers are packed closely together. 00:49:40 So in that sense we have to look at that viral evolution, we have to create the biosecurity around farms like that so that there's not that contact back with human populations and we have to address all of those issues. But no, right now the evidence that we have doesn't suggest that this variant is in any way different in the way it behaves. It may have a slightly different signature but it is still the same virus. What we have to evaluate over time is whether that virus has any difference in transmission or clinical severity or whether it has any implication for diagnostics of vaccines but we're a long, long way away from making any determination of that kind and Soumya may comment on the vaccine issue. I know this concerns people but I believe we're a long way from making any determination there and Soumya is an expert in this field so I will defer to her knowledge and wisdom. SS Maybe just to add to what Mike has said, I think it's too early to really jump to conclusions as to the indications of what these specific mutations have either for transmission or for the severity of the disease, clinical presentation or indeed for the immune response and potentially vaccine efficacy. So I think so far we've been tracking these mutations. As you know, we have over 170,000 whole-genome sequences now in GISAID and there's scientific work going on around the world and WHO's leading a group as well that's a group of evolutionary biologists and experts on bioinformatics that's constantly tracking these changes in mutations that are happening and we've seen plenty of them. 00:51:26 So I think we need to wait and see what the implications are but I don't think we should come to any conclusions about whether this particular mutation is going to impact vaccine efficacy or not. We don't have any evidence at the moment that it would but we will update you as we get more information. FC Thank you, Dr Swaminathan. I would like now to invite Laurent Cirot from ATS, Swiss news agency, to ask the next question. Laurent, can you hear me? LA Yes. Can you hear me, Fadela? FC Yes, very well. Go ahead, please. LA Thank you. Thank you for taking my question. There's been in recent days a small controversy here in Switzerland about the solidarity between the different linguistic regions in the way hospitals and health centres accept treating people from other centres so the solidarity between health centres. 00:52:26 I'd like to know whether you have a global assessment on the way it works worldwide and maybe also in Europe. Thank you. MR It's difficult to make any specific comment on the specific situation but if we look at this globally we've actually seen huge solidarity within countries and between countries especially when it comes to the clinical care of patients. We've seen thousands of health workers go to areas to provide assistance when that was needed in particular areas and we've seen transfer of patients out of areas to areas where they could receive better clinical care or intensive care as emergency rooms and intensive care units came under pressure in certain areas. The DG speaks all the time about solidarity and science, solidarity and solutions. We don't do good science without solidarity. We don't do good clinical care without solidarity and frankly we don't behave ourselves in communities to prevent the transmission of infection without that solidarity. 00:53:29 We need to support each other as individuals, as communities and within health systems but our overall assessment globally, I would suggest, indicates a massive outpouring of scientific and healthcare solidarity in many federalised systems, putting aside the differences between the systems and any rivalries or difficulties and finding ways to help each other. It's not always easy because sharing resources in a crisis is tough when you're not quite sure how you're going to need those resources potentially in a few days' time. That is a very difficult thing to do, it's a very big step from an operational, planning point of view and also spiritually, just to offer others assistance where you may need those resources yourself. We encourage people to continue to do that going forward. FC Thank you, Dr Ryan. I would like now to invite the reporter from Jakarta Post, Ardila Svakria, to ask the next question. Ardila, can you hear me? Jakarta Post. AR Hi, can you hear me? FC Yes, very well. Go ahead, please. AR Okay. Can I still address a question to the Indonesian Minister? 00:54:58 FC Yes, he's still with us. Please go ahead. AR Okay. As Dr Tedros said, the IAR has allowed countries to learn about what worked and what did not work in the countries in terms of their response to COVID-19. I'd like to ask the Minister; from the IAR that Indonesia has conducted what didn't work and how...? FC Ardila, you were cut off. Can you hear me? AR Hi, can you hear me? FC Yes. We lost you. Can you just repeat the last part of your question? AR Okay. From the AIR that Indonesia has conducted, what kind of response, did it work in Indonesia and how the Government has been trying with it [?]. Thank you. FC Yes, thank you, Ardila. Minister of Indonesia, did you hear the question? TAP Yes. Thank you very much, Ardila, from Jakarta Post. IAR is intended to be a platform for continual learning. Based on the IAR recommendation we have expanded the laboratories network and referral hospital as well as conducting massive recruitment of contact tracers and training for contact tracing. 00:56:50 The Ministry of Health and all of the Government of Indonesia has conducted efforts in the nine pillars of the COVID-19 strategic response. The IAR serves as a tool to review our response systematically. It identifies strengths and gaps so that we can in future improve our response. One of the challenges during IAR is because of [unclear] social restriction we have to conduct the IAR via videoconference so there are challenges in getting the participation of the [unclear]. I affirm we have managed to combine the IAR with the use of participant perception surveys filled by all participants represented at the review. In this way we were able to capture a more in-depth and comprehensive input from the participants. Thank you. 00:58:04 FC Thank you, Honourable Minister from Indonesia. We have now a journalist joining from South Africa, from City Press. You have the floor. I think it's Wiya Mkize from City Press, South Africa. WI Yes, good afternoon, can you hear me? FC Very well. Go ahead, please. WI Hi. It's Wiya Mkize from City Press newspaper in South Africa. I have a question for Minister Mkize. He had spoken about the country having an indication of clusters of cases in certain areas. We've seen a report showing that in the Eastern Cape alone there were 758 new cases on Thursday and growing hospitalisation. Is there a confirmed resurgence in that province and can you talk us through that province's plan to mitigate against that resurgence and the factors that are influencing this rise in cases? Thank you. FC Thank you, Wiya. Honourable Minister of South Africa, Minister Mkize, are you online? ZM Yes, thank you very much. Thank you for the question. Indeed we are observing a number of areas where there are cluster outbreaks that are showing. 00:59:32 The areas where we've picked this up have been some areas such as in the Western Cape and the Eastern Cape. We get these clusters and therefore we have to go in and make an assessment as to to what extent they constitute cumulatively what we should call a resurgence. So we are observing the fact that there's activity that is showing the numbers that are a bit higher in some of the areas such as Nelson Mandela Bay and some of the border areas bordering the two provinces of the east and west provinces, maybe too some of the movement, particularly since now farm workers and so on. So there's work that's being done on a regular basis so that you can classify it as a resurgence when we've got all the factors properly evaluated. But there are clusters, we are looking at them and at the right time we'll be able to indicate whether in fact they're something that requires additional action. 01:00:34 The provinces; there's quite an improvement in the Eastern Cape with the new team that we've set in place to go and help to improve the response and so over the past since July coming this way we have seen a lot of improvement and therefore some of the capacity in terms of bed numbers, oxygen utilisation have actually not been ever exceeded. So we do believe that if there's any change we should be able to respond as we have done in the past. Thank you very much. FC Thank you. I would like now to pass the floor to Mark Webster from CGTN. Mark, can you hear me? MA Thank you. I'd really like to follow up on the Danish question - Mark Webster from CGTN. As I understood it this particular mutation doesn't post any immediate danger according to your experts so therefore presumably it would be totally premature to carry out a mass cull of mink. FC Thank you, Mark. MK Thank you. I didn't actually hear a question in there but what I can say is the situation as we know it, as we've described. There are variations in these viruses that are identified in mink and in the specific situation that we're talking about in Denmark there's one virus variant that has been found in 12 individuals, 12 humans. 01:02:14 So what the authorities are doing is they are looking for the extent of infection if there are other cases with this particular variant. The reason that this variant is of concern is some preliminary studies which must be confirmed and there are more studies that need to be done to really understand if there are any changes in the behaviour of this particular variant and if there are any implications down the road as we had described, as it relates to diagnostics, therapeutics and vaccines. But there is a process that's in place and the question that was earlier was what does this mean for the everyday person and how worried should I be. I think what is important for the everyday person is to understand that there is surveillance that is ongoing, that is looking. There are full genome sequences that are being shared and if there's anything I can stress it's that we need more sequences to be shared. As this virus continues to circulate the globe, as we see it in mink in different populations those sequences need to be shared because they need to be evaluated, they need to be studied, they need to be discussed and that needs to be continue and we need scientists to be able to continue to share those sequences so that's really, really important. 01:03:23 But in the current situation what the Danish authorities have outlined are a series of steps that they have put in place to limit the ability of the virus or these viruses - and there are different variants that are found in mink - to spill over and to pass from minks to humans because we don't want to establish a new animal reservoir for this virus. So those are the steps that are being put in place, and also to make sure that we are still continuing to do surveillance in humans, increase sequencing capacity in many different countries. I think that's what's important in the situation now and for you to understand that there is a process in place to evaluate each and every one of these mutations to determine their importance. MR Yes, and just to add in terms of adding to your question about the decision of the Danish health authorities - and Peter alluded to this earlier and this happens all over the world every day as we raise animals around the world. 01:04:26 The issue in terms of the decision you make whether to cull or not cull is based on a number of things; first of all the extent of that infection in that animal population and the concerns you may have about viral evolution in that animal population, how efficient that particular virus is at spreading within that animal population and how fast it could evolve. The second is the viral risk management around those facilities and there are many countries in the world and many situations; Peter referred to the pig and poultry farming sector, which have very strict virus security in place to prevent any virus jumping back into humans so when you assess that biorisk and biosecurity measures in place. Then the third factor in making that decision is the implications for human health in terms of the likelihood of that disease causing more problems back in the human side in terms of severity or transmission or diagnostics. 01:05:23 Those three factors have to be looked at together. It's not one in isolation and the sovereign authority then has to make a determination between its veterinary and its human health authority and what represents the best decision for veterinary health and for human health. The Danish authorities are looking at all of that evidence, they're making decisions in real time, they're taking strong action and we will continue to work with the scientific community to understand the implications of the findings but in the meantime the Danish authorities have to base their actions on the extent of the virus within that mink population, the biorisk management available around that population and concerns around any health impact in humans. As we've said, we've already seen a number of cases on the human side of the equation and this is then going to take time to fully understand the implications of this, as Soumya alluded to, and that's our job. We have to get on with that on the clinical and scientific and laboratory side of things. FC Thank you. I would like to come back to the first question from a journalist, Travel News Asia, asking specifically about the situation in Thailand. We have the Deputy Director from the Ministry of Health of Thailand who'd like to take this question. Can you hear me, Dr Tanaka? You are muted. Can you please unmute yourself? Yes, please go ahead. 01:07:05 TP Thank you very much for the question and giving us an opportunity to answer this question. In Thailand we're trying to reduce the quarantine days down from 14 days to ten days but not for every country. We plan to implement it for the low-risk countries first and then after ten days the travellers can come out of quarantine. But they still need to report to the Minister of Public Health and they will have what we call limited travel. They can travel but their schedule has to be reported to the authorities and they can travel to only a few limited spots and they cannot go into a large gathering or they cannot go into certain places where we've still prohibited them from going. So that is our plan, to reduce the quarantine days to ten days and we hope that with this plan we can still be very safe in checking the travel into our countries and prevent the cases from increasing as well. Thank you very much. 01:08:29 FC Thank you. I would like just to give the full name of the speaker; Dr Taranaki Plipat. He's Deputy Director-General, Department of Disease Control, Ministry of Public Health, Thailand. Thank you, Doctor. I would like now to ask the reporter from GG Press to ask the next question. Can you hear me? UM Yes, I can hear you. Can you hear me? FC Yes, very well. Go ahead, please. UM Okay. Thank you very much for taking my question. My question is about Taiwan and I'd appreciate it if Dr Tedros could answer this. Many countries and associations are again demanding WHO accept Taiwan as an observer to the World Health Assembly next week. So my question is, I'd like to know if you are going to invite Taiwan as an observer to the meeting. If not please tell us why. Thank you very much. FC Thank you. I would like to invite Steve Solomon, Principal Legal Officer, to take this question. SS Thank you very much and thank you for that question. The resumed session of the 73rd World Health Assembly will begin on Monday so this question is very timely but before I answer your question - and I will answer your question - related to that, very importantly, is the issue of technical health issues. On technical health issues WHO works with everyone everywhere; in Taiwan, China, everywhere and this helps ensure that there is no gap in achieving one of the principles of our constitution. 01:10:19 I'm going to read that principle because it is so important. The principle is that the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition. This principle is written into the DNA of WHO staff so our technical work with Taiwanese health experts is very broad-based, it focuses on COVID, it focuses on a broad range of health areas. We've shared that with you. You can find a list of these areas where we co-operate technically with Taiwanese health experts and health authorities on our website. That is available and that is kept updated but I will take a moment to give three important new developments in those areas of our work with Taiwanese health authorities. First we are working with them through the COVAX facility; that is the facility that is designed to ensure equity with respect to the development of and access to COVID vaccines. 01:11:28 We're working with them through the pandemic influenza preparedness framework, which is a framework designed to strengthen protection and safeguards with respect to pandemic influenza and we are working with them through direct discussions and conferences and in fact with Dr Maria Van Kerkhove we briefed Taiwanese CDC officials just this week and that is an ongoing effort. Now as to your question with respect to observership, with respect to observership that is participation in the governing bodies of the World Health Organization, particularly the World Health Assembly, what WHO is is the key point to understand here. WHO is an intergovernmental organisation. This means that countries make the policy decisions. The DG and the secretariat must operate within the context of those decisions and in accordance with those decisions. In 1972 member states at the World Health Assembly passed a resolution which says that the People's Republic of China is the - quote - only legitimate representative of China to WHO. That resolution still stands and Taiwanese involvement at the Health Assembly as an observer continues to be a question for member states. 01:12:59 In fact since 1997 this question has come up 14 times and each time member states have decided against inviting Taiwan as an observer. The question will come up again at the assembly on Monday. There is a proposal for what is called a supplementary agenda item. That proposal is made by 14 member states. Again if you're interested in the list of member states it is on our website. That proposal is procedurally correct under the constitution because this is an issue for member states. In sum, observership is a question for member states and technical work of the secretariat, of the Director-General with everyone everywhere continues to ensure that we advance the principle of health for all as it it's embodied in our constitution. Thank you. FC Thank you so much. This press conference has now been in progress for more than one hour but I would like to give the floor to Dr Van Kerkhove for additional information. 01:14:19 MK Thanks, Fadela. I'll be very brief. Just to supplement what Steve has said on the interaction with Taiwan scientific colleagues, there has been an active, really wonderful exchange with colleagues and scientists from Taiwan CDC and others. I've briefed them myself four times throughout this pandemic and it's been an exchange of sharing the global situation and some of the recent concerns we have but also hearing from them as well how they've handled the pandemic and then an exchange of lots of questions back and forth. So it's been a really good, very positive exchange and also we have a number of scientists who are part of our technical networks, as Steve has said, and who have been part of our technical networks throughout. So on a scientific level it's really great and, as Steve said again and as the Director-General said, we work with everyone everywhere. We're all in this together and we are all constantly learning from each other so on the scientific front the solidarity and the unity and the collaboration that we have seen in this is really heartening and it will continue throughout. Thank you. FC Before I pass the floor to Dr Tedros Dr Ryan would like to say something. 01:15:34 MR I just wanted to reflect for a second and it was great to hear the feedback from the countries regarding the interaction review process. We'd just like to recognise the huge amount of work that's gone on inside our organisation with partners to develop the approaches and the methodologies, to learn, adapt and implement from all of the work we've done before on preparedness and to [names], to Stella Chungong, thank you, Stella, for your leadership and to Jaouad Mahjour, our Assistant Director-General for preparedness because this is the work that goes on in this organisation day after day, week after week, year after year, building the capacity within countries to both manage the epidemic response process but also prepare for epidemics. The approach in the IAR is a collaborative approach, it's about learning lessons, not casting blame. It's about doing better; for after-action reviews and others it's about doing better in the next pandemic. The inter-action review process is about doing better next week, next month, it's about saving more lives, it's about stopping more transmission. 01:16:46 It's really important work; it can appear formulaic at times but it is not, it is the essence of success in epidemic response. As a great sports coach once said, if you fail to prepare you're prepared to fail and in this regard I just want to recognise the work of our staff and all of the partners in this regard so that's important for me to say. I don't know, Stella, if you want to say anything on your role in driving this forward. SC Thank you so much, Mark. As we've heard from all Their Excellencies in the countries the intra-action review is really an excellent and great opportunity to bring together every stakeholder from different sectors in a country to analyse collectively the successes, the strengths but also the challenges that have occurred during the pandemic and to course-correct and to adapt their response. But it's also an opportunity to update and validate their strategic response and preparedness plans and to document, apply lessons and share with others. It is really important that we've looked across the 21 countries that have already done their intra-action reviews that a number of strong success stories have come out including the strong co-ordination and leadership that is needed at the highest levels and the whole-of-society approach bringing all sectors including the communities into the discussion. 01:18:31 It is around the flexibility and possibility of repurposing key staff and the workforce towards where the greatest needs are in terms of the pandemic response. It is about ramping up the diagnosis and the testing that occurs in countries but not only ending there; following through with appropriate public health measures in terms of contact tracing, quarantining of contacts and isolation of the sick. Some challenges still have come up across the 21 countries that have conducted IARs and these, especially in the early phases of the response, were the lack of equipment, supplies and robust supply chains and procurement processes have been identified as a challenge and one that should be addressed moving forward for other countries. But also the community-level empowerment and participation as well as the surveillance at the points of entry, providing timely information for evidence-based decision-making and the ability to have in place business continuity plans, especially ones that would allow the provision of essential services in the countries. 01:19:49 So it is really important that countries continue to conduct their intra-action reviews and that they continue also to integrate the findings into their strategic plans but not only that, into their national action plans as we see that many countries are actually facing concomitant outbreaks along with the pandemic. It is important also that countries should continue to share their reports and their experiences with other countries and with the global community. Thank you. MR Thank you, Stella; powerful words. One last thing; I just want to reflect and amplify one message from the Director-General's speech because so many hundreds of thousands of workers, millions of health workers and others have worked for decades to bring measles under control and try to eradicate polio. The appeal today being launched by WHO and UNICEF is close to the heart of so many national and international health workers. We've got so close to polio eradication. We're getting closer to measles though we've taken a few steps back. We need to reignite immunisation as the primary measure within primary healthcare. It is absolutely vital we don't potentially win the battle against COVID and lose the battle against polio or measles at the same time. Too many people have sacrificed too much. 01:21:25 So I would just add my voice to the call today to use polio and measles as a way of reigniting our immunisation systems and in doing that we will, number one, reach some very cherished goals that we have; number two, we will build the power and the agility and the flexibility and the effectiveness of the immunisation systems that we're going to need to be able to be successful in the delivery and safe vaccination against COVID-19. These two objectives are mutually aligned, they're mutually supportive and polio eradication and measles elimination represent some of the most cherished goals of mankind so let's try to get behind the appeal launched by WHO and UNICEF today. Thank you. FC Thank you, Dr Ryan. I would like now to invite Dr Tedros for final comments. Over to you, DG. 01:22:22 TAG Thank you. I'd like to first of all concur with what Mike and Stella have said and I'd also like to thank His Excellency, Deputy Prime Minister Charnvirakul, His Excellency, Minister Mkhize, and His Excellency, Minister Putranto for joining us today and for sharing their experience of intra-action reviews. Thank you so much also to all journalists who joined us today and see you in our next presser. Thank you. Have a nice day. FC Thank you, Dr Tedros. I would like to remind journalists that we will be sending the audio file and Dr Tedros' remarks right after the press conference. The full transcript will be posted tomorrow on the WHO website. Finally, as you know, next week is the resumed session of the World Health Assembly from 9th to 14th November. I would like to inform journalists that no press conferences on COVID-19 are planned for next week but of course if the need is to have one we will keep you informed. Thank you and have a great day. 01:24:02

Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine.

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post-vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP-IPV-Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post-vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G-CSF, IL-1RA and IL-6. Post-vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin-3, -5 and GM-CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine.

Metagenomic sequencing of stool samples in Bangladeshi infants: virome association with poliovirus shedding after oral poliovirus vaccination.

The potential role of enteric viral infections and the developing infant virome in affecting immune responses to the oral poliovirus vaccine (OPV) is unknown. Here we performed viral metagenomic sequencing on 3 serially collected stool samples from 30 Bangladeshi infants following OPV vaccination and compared findings to stool samples from 16 age-matched infants in the United States (US). In 14 Bangladeshi infants, available post-vaccination serum samples were tested for polio-neutralizing antibodies. The abundance (p = 0.006) and richness (p = 0.013) of the eukaryotic virome increased with age and were higher than seen in age-matched US infants (p < 0.001). In contrast, phage diversity metrics remained stable and were similar to those in US infants. Non-poliovirus eukaryotic virus abundance (3.68 log10 vs. 2.25 log10, p = 0.002), particularly from potential viral pathogens (2.78log10 vs. 0.83log10, p = 0.002), and richness (p = 0.016) were inversely associated with poliovirus shedding. Following vaccination, 28.6% of 14 infants tested developed neutralizing antibodies to all three Sabin types and also exhibited higher rates of poliovirus shedding (p = 0.020). No vaccine-derived poliovirus variants were detected. These results reveal an inverse association between eukaryotic virome abundance and poliovirus shedding. Overall gut virome ecology and concurrent viral infections may impact oral vaccine responsiveness in Bangladeshi infants.

Association of Routine Infant Vaccinations With Antibody Levels Among Preterm Infants.

Importance: The standard schedule of national immunization programs for infants may not be sufficient to protect extremely and very preterm infants. Objective: To evaluate the immunogenicity of routine vaccinations administered to preterm infants. Design, Setting, and Participants: A multicenter, prospective, observational cohort study of preterm infants stratified according to gestational age recruited from 8 hospitals across the Netherlands between October 2015 and October 2017, with follow-up until 12 months of age (October 2018). In total, 296 premature infants were enrolled and compared with a control group of 66 healthy term infants from a 2011 study, immunized according to the same schedule with the same vaccines. Exposures: Three primary doses of the diphtheria-tetanus toxoids-acellular pertussis-inactivated poliomyelitis-Haemophilus influenza type b-hepatitis B combination vaccine were given at 2, 3, and 4 months after birth followed by a booster at 11 months and a 10-valent pneumococcal conjugate vaccine at 2, 4, and 11 months after birth. Main Outcomes and Measures: Primary end points were (1) proportion of preterm infants who achieved IgG antibody against vaccine antigens at concentrations above the internationally defined threshold for protection after the primary series and booster dose and (2) serum IgG geometric mean concentrations after the primary series and booster vaccination. Proportions and geometric mean concentrations were compared in preterm infants and the control group of term infants. Results: Of 296 preterm infants (56.1% male; mean gestational age, 30 weeks), complete samples before vaccination, 1 month after the primary series, and 1 month after the booster were obtained from 220 preterm infants (74.3%). After the primary series, the proportion of preterm infants across all gestational age groups who achieved protective IgG antibody levels against pertussis toxin, diphtheria, tetanus and 6 of 10 pneumococcal serotypes varied between 83.0% and 100%, Haemophilus influenzae type b between 34.7% and 46.2% (40.6% among all preterm infants overall), and pneumococcal serotypes 4, 6B, 18C, and 23F between 45.8% and 75.1%. After the booster dose, protective antibody levels were achieved in more than 95% of all preterm groups, except for Haemophilus influenzae type b (88.1%). In general, geometric mean concentrations of all vaccine-induced antibodies were significantly lower in all preterm infants vs term infants, except for pertussis toxin and pneumococcal serotypes 4 and 19F after the primary series and booster vaccination. Conclusions and Relevance: Among preterm infants, administration of routine vaccinations during the first year of life was associated with protective antibody levels against most antigens in the majority of infants after the primary series and booster, except for Haemophilus influenzae type b. However, antibody concentrations were generally lower among preterm infants compared with historical controls.

[Introduction of pertussis vaccination during pregnancy]. / Invoering van een kinkhoestvaccinatie voor zwangeren.

Pertussis is an endemic disease in the Netherlands. In order to protect infants under 6 months of age, women can be vaccinated during pregnancy with a DTaP(-IPV) booster vaccine. After this so-called maternal vaccination, pertussis antibodies are passed through the placenta to the unborn child, who will be protected after birth. The vaccine is offered as a part of the national vaccination programme (Rijksvaccinatieprogramma, RVP) since 16 December 2019. Children of maternally vaccinated women will follow a different vaccination schedule, namely the 3-5-11-months schedule. This schedule change applies to the DTaP-IPV-HiB-HepB combination vaccine and the 10-valent pneumococcal (PCV10) vaccine. High-risk groups and children of unvaccinated mothers will follow the 2-3-5-11 months schedule. Maternal vaccination is offered from 22 weeks of gestation in the Netherlands. This timing is logistically feasible. We have seen that women already got themselves actively vaccinated during pregnancy before the inclusion of the vaccine in the RVP.

Immunogenicity of three sequential schedules with Sabin inactivated poliovirus vaccine and bivalent oral poliovirus vaccine in Zhejiang, China: an open-label, randomised, controlled trial.

BACKGROUND: The globally synchronised introduction of inactivated poliovirus vaccine (IPV) and replacement of trivalent oral poliovirus vaccine (OPV) with bivalent OPV (bOPV) were successfully implemented in China's routine immunisation programme in May, 2016. In response to the global shortage of Salk-strain IPV, Sabin-strain IPV production was encouraged to develop and use in low-income and middle-income countries. We assessed the immunogenicity of the current routine poliovirus vaccination schedule in China and compared it with alternative schedules that use Sabin-strain IPV (sIPV) and bOPV. METHODS: This open-label, randomised, controlled trial recruited healthy infants aged 60-75 days from two centres in Zhejiang, China. Eligible infants were full-term, due for their first polio vaccination, weighed more than 2·5 kg at birth, were healthy on physical examination with no obvious medical conditions, and had no contraindications to vaccination. Infants were randomly assigned (1:1:1) using permuted block randomisation (block size of 12) to one of three polio vaccination schedules, with the first, second, and third doses given at ages 2 months, 3 months, and 4 months, respectively: sIPV-bOPV-bOPV (1sIPV+2bOPV group; current regimen), sIPV-sIPV-bOPV (2sIPV+1bOPV group), or sIPV-sIPV-sIPV (3sIPV group). The primary endpoint was the proportion of infants with seroconversion to each of the three poliovirus serotypes 1 month after the third dose. Serious and medically important adverse events were monitored for up to 30 days after each vaccination. We assessed immunity in the per-protocol population (all children who completed all three vaccinations and had pre-vaccination and post-vaccination laboratory data) and safety in all children who received at least one dose of study vaccine. This trial is registered with Clinicaltrials.gov, NCT03147560. RESULTS: Between May 1, 2016, and Dec 1, 2017, we enrolled and randomly assigned 528 eligible infants to one of the three treatment groups (176 in each group); 473 infants (158 in the 1sIPV+2bOPV group, 152 in the 2sIPV+1bOPV group, and 163 in the 3sIPV group) were included in the per-protocol population. 100% seroconversion against poliovirus types 1 and 3 was observed in all three groups. Infants who received an immunisation schedule containing bOPV had significantly higher antibody titres against poliovirus types 1 and 3 than did the sIPV-only group (2048 in all three treatment groups; p<0·0001). Seroconversion against type 2 poliovirus was observed in 98 (62%) infants in the 1sIPV+2bOPV group, 145 (95%) infants in the 2sIPV+1bOPV group, and 161 (99%) infants in the 3sIPV group. No serious adverse events occurred during the study; 14 minor, transient adverse events were observed, with no significant differences across study groups. INTERPRETATION: All three study schedules were well tolerated and highly immunogenic against poliovirus types 1 and 3. Schedules containing two or three sIPV doses had higher seroconversion rates against poliovirus type 2 than did the schedule with a single dose of sIPV. Our findings support inclusion of two sIPV doses in the routine poliovirus vaccination schedule in China to provide better protection against poliovirus type 2 than provided by the current regimen. FUNDING: Chinese Center for Disease Control and Prevention and China National Biotec Group Company.

Infant vaccine co-administration: review of 18 years of experience with GSK's hexavalent vaccine co-administered with routine childhood vaccines.

INTRODUCTION: The benefits of vaccine co-administration include improved vaccine acceptance and uptake resulting in an increased coverage and protection against multiple childhood diseases, with minimal medical visits. The diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis-Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) has been available for more than 19 years and is recommended for co-administration with several other infant vaccines. AREAS COVERED: This is a comprehensive review (34 studies, 21,000 participants) describing the immunogenicity and safety of DTaP-HBV-IPV/Hib when co-administered with 12 different vaccines in infants including pneumococcal, meningococcal, rotavirus or measles-mumps-rubella-varicella. EXPERT OPINION: Interactions among co-administered vaccines are complex. Therefore, co-administration data are critical before a vaccination regimen can be recommended. Co-administration of DTaP-HBV-IPV/Hib with other routinely administered vaccines was associated with high percentages of children achieving seroprotection/vaccine response against DTaP-HBV-IPV/Hib antigens. In addition, co-administration was not associated with clinically significant interference in immune responses to co-administered vaccines and was well tolerated. Increased systemic reactions observed with some combinations (DTaP-HBV-IPV/Hib + pneumococcal conjugate or meningococcal serogroup B vaccines) were mitigated by prophylactic paracetamol administration. The data reported here, which represent the most frequently used co-administrations of DTaP-HBV-IPV/Hib worldwide, support the concomitant administration of DTaP-HBV-IPV/Hib with other routinely recommended infant vaccines.