Meningococcal ACWYX Conjugate Vaccine in 2-to-29-Year-Olds in Mali and Gambia.

BACKGROUND: An effective, affordable, multivalent meningococcal conjugate vaccine is needed to prevent epidemic meningitis in the African meningitis belt. Data on the safety and immunogenicity of NmCV-5, a pentavalent vaccine targeting the A, C, W, Y, and X serogroups, have been limited. METHODS: We conducted a phase 3, noninferiority trial involving healthy 2-to-29-year-olds in Mali and Gambia. Participants were randomly assigned in a 2:1 ratio to receive a single intramuscular dose of NmCV-5 or the quadrivalent vaccine MenACWY-D. Immunogenicity was assessed at day 28. The noninferiority of NmCV-5 to MenACWY-D was assessed on the basis of the difference in the percentage of participants with a seroresponse (defined as prespecified changes in titer; margin, lower limit of the 96% confidence interval [CI] above -10 percentage points) or geometric mean titer (GMT) ratios (margin, lower limit of the 98.98% CI >0.5). Serogroup X responses in the NmCV-5 group were compared with the lowest response among the MenACWY-D serogroups. Safety was also assessed. RESULTS: A total of 1800 participants received NmCV-5 or MenACWY-D. In the NmCV-5 group, the percentage of participants with a seroresponse ranged from 70.5% (95% CI, 67.8 to 73.2) for serogroup A to 98.5% (95% CI, 97.6 to 99.2) for serogroup W; the percentage with a serogroup X response was 97.2% (95% CI, 96.0 to 98.1). The overall difference between the two vaccines in seroresponse for the four shared serogroups ranged from 1.2 percentage points (96% CI, -0.3 to 3.1) for serogroup W to 20.5 percentage points (96% CI, 15.4 to 25.6) for serogroup A. The overall GMT ratios for the four shared serogroups ranged from 1.7 (98.98% CI, 1.5 to 1.9) for serogroup A to 2.8 (98.98% CI, 2.3 to 3.5) for serogroup C. The serogroup X component of the NmCV-5 vaccine generated seroresponses and GMTs that met the prespecified noninferiority criteria. The incidence of systemic adverse events was similar in the two groups (11.1% in the NmCV-5 group and 9.2% in the MenACWY-D group). CONCLUSIONS: For all four serotypes in common with the MenACWY-D vaccine, the NmCV-5 vaccine elicited immune responses that were noninferior to those elicited by the MenACWY-D vaccine. NmCV-5 also elicited immune responses to serogroup X. No safety concerns were evident. (Funded by the U.K. Foreign, Commonwealth, and Development Office and others; ClinicalTrials.gov number, NCT03964012.).

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

5-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in Bangladeshi children (TyVOID): a cluster randomised trial.

BACKGROUND: WHO currently recommends a single dose of typhoid conjugate vaccine (TCV) in high-burden countries based on 2-year vaccine efficacy data from large randomised controlled trials. Given the decay of immunogenicity, the protection beyond 2 years is unknown. We therefore extended the follow-up of the TyVAC trial in Bangladesh to assess waning of vaccine protection to 5 years after vaccination. METHODS: We conducted a cluster randomised controlled trial (TyVAC; ISRCTN11643110) in Dhaka, Bangladesh, between 2018 and 2021. Children aged 9 months to 15 years were invited to receive a single dose of TCV or Japanese encephalitis vaccine between April 15, 2018, and November 16, 2019, based on the randomisation of their clusters of residence. Children who received the Japanese encephalitis vaccine were invited to receive TCV at the final visit between Jan 6, and Aug 31, 2021, according to the protocol. This follow-on study extended the follow-up of the original trial until Aug 14, 2023. The primary endpoint of this study was to compare the incidence of blood culture-confirmed typhoid between children who received TCV in 2018-19 (the previous-TCV group) and those who received the vaccine in 2021 (the recent-TCV group), to evaluate the relative decline in vaccine protection. We also did a nested study using the test-negative design comparing the recent-TCV and previous-TCV groups with unvaccinated individuals, as well as an immunogenicity study in a subset of 1500 children. FINDINGS: Compared with the recent-TCV group, the previous-TCV group had an increased risk of typhoid fever between 2021-23, with an adjusted incidence rate ratio of 3·10 (95% CI 1·53 to 6·29; p<0·0001), indicating a decline in the protection of a single-dose of TCV 3-5 years after vaccination. The extrapolated vaccine effectiveness in years 3-5 was 50% (95% CI -13 to 78), and was validated using the test-negative design analysis, with a vaccine effectiveness of 84% (74 to 90) in the recent-TCV group and 55% (36 to 68) in the previous-TCV group, compared with unvaccinated individuals. Anti-Vi-IgG responses declined over the study period. The highest rate of decay was seen in children vaccinated at younger than 2 years in the original trial. The inverse correlation between age and the decay of antibodies was also seen in the subgroup analysis of vaccine effectiveness, where the youngest age group (<7 years at fever visits) exhibited the fastest waning, with vaccine effectiveness dropping to 24% (95% CI -29 to 55) at 3-5 years after vaccination. INTERPRETATION: A decline in the protection conferred by a single-dose TCV was observed 3-5 years after vaccination, with the greatest decline in protection and immune responses observed in children vaccinated at younger ages. A booster dose of TCV around school entry age might be needed for children vaccinated while younger than 2 years to sustain protection against typhoid fever during the school years when the risk is the highest. FUNDING: The Bill & Melinda Gates Foundation.

Effect of Pneumococcal Conjugate Vaccines on Viral Respiratory Infections: A Systematic Literature Review.

BACKGROUND: In addition to preventing pneumococcal disease, emerging evidence indicates that pneumococcal conjugate vaccines (PCVs) might indirectly reduce viral respiratory tract infections (RTIs) by affecting pneumococcal-viral interactions. METHODS: We performed a systematic review of interventional and observational studies published during 2000-2022 on vaccine efficacy/adjusted effectiveness (VE) and overall effect of PCV7, PCV9, PCV10, or PCV13 against viral RTIs. RESULTS: Sixteen of 1671 records identified were included. Thirteen publications described effects of PCVs against viral RTIs in children. VE against influenza ranged between 41% and 86% (n = 4), except for the 2010-2011 influenza season. In a randomized controlled trial, PCV9 displayed efficacy against any viral RTI, human seasonal coronavirus, parainfluenza, and human metapneumovirus. Data in adults were limited (n = 3). PCV13 VE was 4%-25% against viral lower RTI, 32%-35% against coronavirus disease 2019 outcomes, 24%-51% against human seasonal coronavirus, and 13%-36% against influenza A lower RTI, with some 95% confidence intervals spanning zero. No protection was found against adenovirus or rhinovirus in children or adults. CONCLUSIONS: PCVs were associated with protection against some viral RTI, with the strongest evidence for influenza in children. Limited evidence for adults was generally consistent with pediatric data. Restricting public health evaluations to confirmed pneumococcal outcomes may underestimate the full impact of PCVs.

Estimated Population-Level Impact of Pneumococcal Conjugate Vaccines Against All-Cause Pneumonia Mortality Among Unvaccinated in 5 Latin American Countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) provide strong direct protection in children, while limited data are available on their indirect effect on mortality among older age groups. This multicountry study aimed to assess the population-level impact of pediatric PCVs on all-cause pneumonia mortality among children ≥5 years of age, and invasive pneumococcal disease (IPD) cases in Chile. METHODS: Demographic and mortality data from Argentina, Brazil, Chile, Colombia, and Mexico were collected considering the ≥ 5-year-old population, from 2000 to 2019, with 1 795 789 deaths due to all-cause pneumonia. IPD cases in Chile were also evaluated. Time series models were employed to evaluate changes in all-cause pneumonia deaths during the postvaccination period, with other causes of death used as synthetic controls for unrelated temporal trends. RESULTS: No significant change in death rates due to all-cause pneumonia was detected following PCV introduction among most age groups and countries. The proportion of IPD cases caused by vaccine serotypes decreased from 29% (2012) to 6% (2022) among people aged ≥65 years in Chile. DISCUSSION: While an effect of PCV against pneumonia deaths (a broad clinical definition that may not be specific enough to measure indirect effects) was not detected, evidence of indirect PCV impact was observed among vaccine-type-specific IPD cases.

Outpatient Visits and Antibiotic Use Due to Higher-Valency Pneumococcal Vaccine Serotypes.

BACKGROUND: In 2022-2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in US children (≤17 years) from 2016-2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts. METHODS: We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national health care surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses. RESULTS: Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval, 1.8-3.9) visits and 2.4 (95% CI, 1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (95% CI, 11.2-20.4) visits and 13.2 (95% CI, 9.9-18.0) antibiotic prescriptions annually per 1000 children. PCV15/20-additional serotypes account for 0.4% (95% CI, 0.2%-0.6%) and 2.1% (95% CI, 1.5%-3.0%) of pediatric outpatient antibiotic use. CONCLUSIONS: Compared with PCV15-additional serotypes, PCV20-additional serotypes account for > 5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.

Hearing loss in Australian First Nations children at 6-monthly assessments from age 12 to 36 months: Secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules.

BACKGROUND: In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. METHODS AND FINDINGS: In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. CONCLUSIONS: In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01735084 and NCT01174849.

Estimating pneumococcal carriage dynamics in adults living with HIV in a mature infant pneumococcal conjugate vaccine programme in Malawi, a modelling study.

BACKGROUND: Adults living with human immunodeficiency virus (ALWHIV) receiving antiretroviral therapy (ART) exhibit higher pneumococcal carriage prevalence than adults without HIV (HIV-). To assess factors influencing high pneumococcal carriage in ALWHIV, we estimated pneumococcal carriage acquisition and clearance rates in a high transmission and disease-burdened setting at least 10 years after introducing infant PCV13 in routine immunisation. METHODS: We collected longitudinal nasopharyngeal swabs from individuals aged 18-45 in Blantyre, Malawi. The study group included both HIV- individuals and those living with HIV, categorised based on ART duration as either exceeding 1 year (ART > 1y) or less than 3 months (ART < 3 m). Samples were collected at baseline and then weekly for 16 visits. To detect pneumococcal carriage, we used classical culture microbiology, and to determine pneumococcal serotypes, we used latex agglutination. We modelled trajectories of serotype colonisation using multi-state Markov models to capture pneumococcal carriage dynamics, adjusting for age, sex, number of under 5 year old (< 5y) children, social economic status (SES), and seasonality. RESULTS: We enrolled 195 adults, 65 adults in each of the study groups. 51.8% were females, 25.6% lived with more than one child under 5 years old, and 41.6% lived in low socioeconomic areas. The median age was 33 years (IQR 25-37 years). The baseline pneumococcal carriage prevalence of all serotypes was 31.3%, with non-PCV13 serotypes (NVT) at 26.2% and PCV13 serotypes (VT) at 5.1%. In a multivariate longitudinal analysis, pneumococcal carriage acquisition was higher in females than males (hazard ratio [HR], NVT [1.53]; VT [1.96]). It was also higher in low than high SES (NVT [1.38]; VT [2.06]), in adults living with 2 + than 1 child < 5y (VT [1.78]), and in ALWHIV on ART > 1y than HIV- adults (NVT [1.43]). Moreover, ALWHIV on ART > 1y cleared pneumococci slower than HIV- adults ([0.65]). Residual VT 19F and 3 were highly acquired, although NVT remained dominant. CONCLUSIONS: The disproportionately high point prevalence of pneumococcal carriage in ALWHIV on ART > 1y is likely due to impaired nasopharyngeal clearance, which results in prolonged carriage. Our findings provide baseline estimates for comparing pneumococcal carriage dynamics after implementing new PCV strategies in ALWHIV.

Use of 21-Valent Pneumococcal Conjugate Vaccine Among U.S. Adults: Recommendations of the Advisory Committee on Immunization Practices - United States, 2024.

On June 17, 2024, the Food and Drug Administration approved 21-valent pneumococcal conjugate vaccine (PCV) (PCV21; CAPVAXIVE; Merck Sharp & Dohme, LLC) for adults aged ≥18 years. PCV21 does not contain certain serotypes that are included in other licensed pneumococcal vaccines but adds eight new serotypes. The Advisory Committee on Immunization Practices (ACIP) recommends use of a PCV for all adults aged ≥65 years, as well as adults aged 19-64 years with certain risk conditions for pneumococcal disease if they have not received a PCV or whose vaccination history is unknown. Previously, options included either 20-valent PCV (PCV20; Prevnar20; Wyeth Pharmaceuticals, Inc.) alone or a 15-valent PCV (PCV15; VAXNEUVANCE; Merck Sharp & Dohme, LLC) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23; Pneumovax23; Merck Sharp & Dohme, LLC). Additional recommendations for use of PCV20 exist for adults who started their pneumococcal vaccination series with 13-valent PCV (PCV13; Prevnar13; Wyeth Pharmaceuticals, Inc.). The ACIP Pneumococcal Vaccines Work Group employed the Evidence to Recommendations framework to guide its deliberations on PCV21 vaccination among U.S. adults. On June 27, 2024, ACIP recommended a single dose of PCV21 as an option for adults aged ≥19 years for whom PCV is currently recommended. Indications for PCV have not changed from previous recommendations. This report summarizes evidence considered for these recommendations and provides clinical guidance for use of PCV21.

Prevalence, spatial distribution and determinants of complete childhood pneumococcal conjugate vaccination in Ethiopia: spatial and multilevel analyses.

INTRODUCTION: Pneumococcal disease is a serious global public health concern. The primary causative agent of severe illnesses such as pneumonia, meningitis, acute otitis media, and bacteremia is the pneumococcus bacterium. The pneumococcal conjugate vaccine is a key strategy to reduce the burden of pneumococcal disease. Understanding the spatial distribution of complete childhood pneumococcal conjugate vaccine utilization and its associated factors is crucial for designing strategies to improve vaccination implementation. Therefore, this study aimed to determine the spatial distribution of complete childhood pneumococcal conjugate vaccination coverage and identify its determinants in Ethiopia. METHOD: A spatial and multilevel analysis was conducted using data from the 2019 Ethiopian Mini Demographic and Health Survey. The analysis included a total of 2,055 weighted children. The association between the outcome variable and the explanatory variables was determined by calculating adjusted odds ratios at a 95% confidence interval. Explanatory variables were considered significantly associated with the outcome if the p-value was less than 0.05. RESULT: The prevalence of complete childhood pneumococcal conjugate vaccination in Ethiopia was 53.94% (95% CI: 51.77, 56.08). Higher complete childhood pneumococcal vaccination coverage was observed in the Addis Ababa, Tigray, Amhara, Benishangul-Gumuz, and Oromia regions, while lower coverage was seen in the Afar, Somali, and SNNPR regions of Ethiopia. Factors significantly associated with complete childhood pneumococcal conjugate vaccination included maternal age, antenatal care visits, place of delivery, region, community women's literacy level, community poverty level, and community antenatal care utilization. CONCLUSION: The distribution of complete childhood pneumococcal conjugate vaccination exhibited spatial variability across Ethiopia. Approximately half of children aged twelve to thirty-five months received the full dose of the childhood pneumococcal conjugate vaccine in the country. Several factors were identified as statistically significant determinants of complete childhood pneumococcal conjugate vaccination, including maternal age, antenatal care visits, place of delivery, region, community women's literacy level, community poverty level, and community ANC utilization. Therefore, policies and strategies aimed at combating pneumococcal disease should consider these determinants and address areas with low vaccination coverage.

Regional differences in pediatric pneumococcal vaccine schedules for Indigenous children in Canada: an environmental scan.

BACKGROUND: Streptococcus pneumoniae bacteria causes substantial morbidity and mortality worldwide, especially in children under 5 years of age. Prevention of these outcomes by pneumococcal conjugate vaccines (PCV) is an important public health initiative, supported by publicly funded vaccination programs in Canada. While the National Advisory Committee on Immunization (NACI) provides national recommendations for vaccination schedules, decisions on vaccination program delivery are made regionally, creating potential for variability across the country. In addition, defining the groups that are most at risk has become a complex endeavor for provinces and territories in Canada, specifically considering Indigenous children. METHODS: In this environmental scan, we reviewed policy documents, provincial/territorial and international PCV schedules, and scientific literature, and consulted with vaccination program stakeholders and experts from across the country, in order to understand the evolution of PCV vaccination guidelines and policies in Canada and identify whether and how the needs of Indigenous children are addressed. RESULTS: As of March 2023, most regions do not specify particular vaccination requirements for Indigenous children; however, three provinces identify Indigenous children as "high risk" and use varying language to recommend a four dose, rather than the routine three dose, schedule. Our results also draw attention to evidence gaps supporting a differing practice for Indigenous populations. CONCLUSIONS: Future PCV program innovation requires inclusive and clear policies as well as definitive evidence-based policies and practices in order to improve equitable population health.

Health and economic impact of the pneumococcal conjugate vaccine in hindering antimicrobial resistance in China.

Antimicrobial resistance (AMR) poses a serious threat to global public health. However, vaccinations have been largely undervalued as a method to hinder AMR progression. This study examined the AMR impact of increasing pneumococcal conjugate vaccine (PCV) coverage in China. China has one of the world's highest rates of antibiotic use and low PCV coverage. We developed an agent-based DREAMR (Dynamic Representation of the Economics of AMR) model to examine the health and economic benefits of slowing AMR against commonly used antibiotics. We simulated PCV coverage, pneumococcal infections, antibiotic use, and AMR accumulation. Four antibiotics to treat pneumococcal diseases (penicillin, amoxicillin, third-generation cephalosporins, and meropenem) were modeled with antibiotic utilization, pharmacokinetics, and pharmacodynamics factored into predicting AMR accumulation. Three PCV coverage scenarios were simulated over 5 y: 1) status quo with no change in coverage, 2) scaled coverage increase to 99% in 5 y, and 3) accelerated coverage increase to 85% over 2 y followed by 3 y to reach 99% coverage. Compared to the status quo, we found that AMR against penicillin, amoxicillin, and third-generation cephalosporins was significantly reduced by 6.6%, 10.9%, and 9.8% in the scaled scenario and by 10.5%, 17.0%, and 15.4% in the accelerated scenario. Cumulative costs due to AMR, including direct and indirect costs to patients and caretakers, were reduced by $371 million in the scaled and $586 million in the accelerated scenarios compared to the status quo. AMR-reducing benefits of vaccines are essential to quantify in order to drive appropriate investment.

Incidence of Bacteremia and Serious Bacterial Infections in Hyperpyrexic Infants Offered Universal Pneumococcal Conjugate Vaccine 13 and Haemophilus influenzae B Immunization.

BACKGROUND: High fevers, especially in young children, often alarm clinicians and prompt extensive evaluation based on perceptions of increased risk of serious bacterial infection (SBI), and even brain damage or seizure disorders. OBJECTIVE: The aim of this study was to determine the prevalence of SBI in infants aged 3-36 months with fever ≥40.5°C in a population of infants offered universal pneumococcal conjugate vaccine 13 and Haemophilus influenzae B immunization. METHODS: This study is a retrospective review of all infants aged 3-36 months with temperature ≥40.5°C presenting to a tertiary care pediatric emergency department over a 30-month period in an era of universal pneumococcal conjugate 13 and H. influenzae B immunization. RESULTS: SBI was recorded in 54 (21.8%) of 247 study infants, most commonly pneumonia 30 patients (12.1%) and urinary tract infection 16 patients (6.5%). Two patients had positive blood cultures, yielding a bacteremia rate of 0.8%. Patients with SBI had a significantly higher WBC count ( P < 0.0001) and C-reactive protein levels ( P < 0.0001), and were significantly more likely to be hospitalized ( P < 0.0001). DISCUSSION: Although SBI was common (21.8%) in our cohort of hyperpyrexic infants universally offered vaccination with pneumococcal conjugate 13 and H. influenzae B vaccines, bacteremia was a rare finding (0.8%).

Adult Pneumococcal Vaccination in Ghana: Current Status and Future Recommendations - Expert Opinion.

Vaccination programs have proven successful in the prevention and control of infectious diseases among children on a global scale, but the majority of adult populations remain unvaccinated. immunocompromised adults as well as older adults aged low-income countries as Streptococcus pneumoniae infections are associated with substantial morbidity and mortality among 65 years and above. Despite the introduction of pneumococcal conjugate vaccines (PCVs), the burden of vaccine-type serotypes remains high in there are no clear policies for adult vaccination. As per the Global Burden of Disease 2019 report, about 120,000 individuals aged 70 years and older died as a result of LRTIs) in sub-Saharan Africa. A medical advisory board meeting was conducted in April 2022 to discuss the burden of pneumococcal diseases in adults, the current status of policies and practices of adult vaccination, unmet needs, and challenges in Ghana. This expert opinion paper outlines the pneumococcal epidemiology and burden of disease in Ghana, as well as the rationale for adult pneumococcal vaccination. It also highlights the potential barriers to adult vaccination and offers recommendations to overcome these obstacles and enhance vaccine acceptance in Ghana.

Les programmes de vaccination ont prouvé leur succès dans la prévention et le contrôle des maladies infectieuses chez les enfants à l'échelle mondiale, mais la majorité des populations adultes restent non vaccinées. Les infections à Streptococcus pneumoniae sont associées à une morbidité et une mortalité substantielles chez les adultes immunodéprimés ainsi que chez les personnes âgées de 65 ans et plus. Malgré l'introduction des vaccins conjugués contre le pneumocoque (VCP), la charge des sérotypes vaccinaux reste élevée dans les pays à faible revenu car il n'existe pas de politiques claires en matière de vaccination des adultes. Selon le rapport sur la charge mondiale de morbidité de 2019, environ 120 000 personnes âgées de 70 ans et plus sont décédées des suites d'infections des voies respiratoires inférieures (IVRI) en Afrique subsaharienne. Une réunion du conseil consultatif médical a eu lieu en avril 2022 pour discuter du fardeau des maladies pneumococciques chez les adultes, de l'état actuel des politiques et pratiques de vaccination des adultes, des besoins non satisfaits et des défis au Ghana. Cet article d'opinion d'experts présente l'épidémiologie pneumococcique et le fardeau de la maladie au Ghana, ainsi que les arguments en faveur de la vaccination pneumococcique des adultes. Il met également en lumière les obstacles potentiels à la vaccination des adultes et propose des recommandations pour surmonter ces obstacles et améliorer l'acceptation des vaccins au Ghana. MOTS-CLÉS: Maladie pneumococcique, Fardeau de la maladie, Vaccin conjugué contre le pneumocoque, Vaccination des adultes, Streptococcus pneumoniae, Ghana, Défis de la vaccination, Immunisation des adultes, VCP-13, Pneumonie acquise en communauté.

Pneumococcal Vaccines: Host Interactions, Population Dynamics, and Design Principles.

Streptococcus pneumoniae (the pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. Most isolates express a capsule, the species-wide diversity of which has been immunologically classified into ∼100 serotypes. Capsule polysaccharides have been combined into multivalent vaccines widely used in adults, but the T cell independence of the antibody response means they are not protective in infants. Polysaccharide conjugate vaccines (PCVs) trigger a T cell-dependent response through attaching a carrier protein to capsular polysaccharides. The immune response stimulated by PCVs in infants inhibits carriage of vaccine serotypes (VTs), resulting in population-wide herd immunity. These were replaced in carriage by non-VTs. Nevertheless, PCVs drove reductions in infant pneumococcal disease, due to the lower mean invasiveness of the postvaccination bacterial population; age-varying serotype invasiveness resulted in a smaller reduction in adult disease. Alternative vaccines being tested in trials are designed to provide species-wide protection through stimulating innate and cellular immune responses, alongside antibodies to conserved antigens.

Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM197 conjugate vaccine.

Polysaccharide-protein conjugates have been developed to overcome the T-independent response, hyporesponsiveness to repeated vaccination, and poor immunogenicity in infants of polysaccharides. To address the impact of polysaccharide length, typhoid conjugates made with short- and long-chain fractions of Vi polysaccharide with average sizes of 9.5, 22.8, 42.7, 82.0, and 165 kDa were compared. Long-chain-conjugated Vi (165 kDa) induced a response in both wild-type and T cell-deficient mice, suggesting that it maintains a T-independent response. In marked contrast, short-chain Vi (9.5 to 42.7 kDa) conjugates induced a response in wild-type mice but not in T cell-deficient mice, suggesting that the response is dependent on T cell help. Mechanistically, this was explained in neonatal mice, in which long-chain, but not short-chain, Vi conjugate induced late apoptosis of Vi-specific B cells in spleen and early depletion of Vi-specific B cells in bone marrow, resulting in hyporesponsiveness and lack of long-term persistence of Vi-specific IgG in serum and IgG+ antibody-secreting cells in bone marrow. We conclude that while conjugation of long-chain Vi generates T-dependent antigens, the conjugates also retain T-independent properties, leading to detrimental effects on immune responses. The data reported here may explain some inconsistencies observed in clinical trials and help guide the design of effective conjugate vaccines.

Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial.

BACKGROUND: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. METHODS: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110. FINDINGS: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. INTERPRETATION: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. FUNDING: The study was funded by the Bill & Melinda Gates Foundation.

A promising bioconjugate vaccine against hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKp) is globally disseminating as a community-acquired pathogen causing life-threatening infections in healthy individuals. The fact that a dose as little as 50 bacteria is lethal to mice illustrates the dramatic increase of virulence associated with hvKp strains compared with classical K. pneumoniae (cKp) strains, which require lethal doses greater than 107 bacteria. Until recently, these virulent strains were mostly antibiotic-susceptible. However, multidrug-resistant (MDR) hvKp strains have been emerging, spawning a new generation of hypervirulent "superbugs." The mechanisms of hypervirulence are not fully defined, but overproduction of capsular polysaccharide significantly impedes host clearance, resulting in increased pathogenicity of hvKp strains. While there are more than 80 serotypes of K. pneumoniae, the K1 and K2 serotypes cause the vast majority of hypervirulent infections. Therefore, a glycoconjugate vaccine targeting these 2 serotypes could significantly reduce hvKp infection. Conventionally, glycoconjugate vaccines are manufactured using intricate chemical methodologies to covalently attach purified polysaccharides to carrier proteins, which is widely considered to be technically challenging. Here we report on the recombinant production and analytical characterization of bioconjugate vaccines, enzymatically produced in glycoengineered Escherichia coli cells, against the 2 predominant hypervirulent K. pneumoniae serotypes, K1 and K2. The K. pneumoniae bioconjugates are immunogenic and efficacious, protecting mice against lethal infection from 2 hvKp strains, NTUH K-2044 and ATCC 43816. This preclinical study constitutes a key step toward preventing further global dissemination of hypervirulent MDR hvKp strains.

Hib Vaccines: Their Impact on Haemophilus influenzae Type b Disease.

Haemophilus influenzae serotype b (Hib) is an important cause of serious, invasive infections, particularly in young children. Since 1985, a series of vaccines composed of the type b capsular polysaccharide polyribosylribitol phosphate (PRP), followed by PRP conjugated to various proteins, have been licensed for use in the United States and worldwide. The conjugated vaccines offer increased immunogenicity and prolonged durability of immune protection compared to the plain PRP vaccine and increasingly are combined with other childhood vaccines for decreased cost and increased ease of vaccination. Hib vaccines have a very favorable safety profile, have been found to be either cost-saving or cost-effective by many public health agencies, and, in most countries, are initiated during early infancy as part of routine childhood immunization programs. As a result of widespread use of the vaccines, the incidence of Hib infections, and their associated morbidity and mortality, has fallen dramatically across the globe. Yet, many children remain unimmunized or underimmunized against Hib, particularly in limited-resource countries. Future efforts to further reduce the disease burden of Hib infections remain a high priority.