Compensation in Neonatal Clinical Trials: A Perspective.

Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.

A phase III randomized-controlled study of safety and immunogenicity of DTwP-HepB-IPV-Hib vaccine (HEXASIIL®) in infants.

A fully liquid hexavalent containing Diphtheria (D), Tetanus (T) toxoids, whole cell Pertussis (wP), Hepatitis B (Hep B), type 1, 2, 3 of inactivated poliovirus (IPV) and Haemophilus influenzae type b (Hib) conjugate vaccine (DTwP-HepB-IPV-Hib vaccine, HEXASIIL®) was tested for lot-to-lot consistency and non-inferiority against licensed DTwP-HepB-Hib + IPV in an open label, randomized Phase II/III study. In Phase III part, healthy infants received DTwP-HepB-IPV-Hib or DTwP-HepB-Hib + IPV vaccines at 6, 10 and 14 weeks of age. Blood samples were collected prior to the first dose and 28 days, post dose 3. Non inferiority versus DTwP-HepB-Hib + IPV was demonstrated with 95% CIs for the treatment difference for seroprotection/seroconversion rates. For DTwP-HepB-IPV-Hib lots, limits of 95% CI for post-vaccination geometric mean concentration ratios were within equivalence limits (0.5 and 2). Vaccine was well-tolerated and no safety concerns observed.Clinical Trial Registration - CTRI/2019/11/022052.

Immunogenicity and safety of a new quadrivalent HPV vaccine in girls and boys aged 9-14 years versus an established quadrivalent HPV vaccine in women aged 15-26 years in India: a randomised, active-controlled, multicentre, phase 2/3 trial.

BACKGROUND: To meet global cervical cancer elimination efforts, a wider range of affordable and accessible vaccines against human papillomavirus (HPV) are needed. We aimed to evaluate the immunogenicity and safety of a quadrivalent HPV vaccine (targeting HPV types 6, 11, 16, and 18), developed and manufactured by the Serum Institute of India (SIIPL). Here we report outcomes in the 9-14 years cohort. METHODS: This randomised, active-controlled, phase 2/3 trial was conducted at 12 tertiary care hospitals across India. Healthy participants aged 9-14 years or 15-26 years with no history of HPV vaccination were eligible for enrolment. Female participants were randomly assigned (1:1) with an interactive web response system, by use of a central computer-generated schedule and block randomisation (block sizes of 2, 4, 6, and 8), to receive the SIIPL quadrivalent HPV vaccine (Cervavac; SIIPL, Pune, India) or the comparator quadrivalent HPV vaccine (Gardasil; Merck Sharp & Dohme, Harleem, the Netherlands). Participants, investigators, laboratory technicians, and sponsors were masked to treatment allocation of female participants. Male participants were given the SIIPL quadrivalent HPV vaccine in an open-label manner. Study vaccines were administered intramuscularly with a two-dose schedule (at day 0 and 6 months) in the cohort aged 9-14 years, and with a three-dose schedule (at day 0, month 2, and month 6) in the cohort aged 15-26-years. Immunogenicity was assessed 30 days after the last dose by use of multiplexed ELISA. The primary outcome was the non-inferiority of immune response in terms of the geometric mean titre (GMT) of antibodies against HPV types 6, 11, 16, and 18 generated by the SIIPL quadrivalent HPV vaccine in girls and boys (aged 9-14 years) compared with the GMT generated by the comparator quadrivalent HPV vaccine in women aged 15-26 years at month 7 in the modified per-protocol population (ie, all participants who received all doses of study vaccines per assigned treatment group and had both day 0 and 1-month immunogenicity measurements after the last dose following protocol-defined window periods with no major protocol deviations). Non-inferiority was established if the lower bound of the 98·75% CI of the GMT ratio was 0·67 or higher. The co-primary outcome of occurrence of solicited adverse events (within 7 days of each dose) and unsolicited adverse events (up to 30 days after the last dose) was assessed in all participants who were enrolled and received at least one dose of study vaccine. The trial is registered with the Clinical Trials Registry - India (CTRI/2018/06/014601), and long-term follow-up is ongoing. FINDINGS: Between Sept 20, 2018, and Feb 9, 2021, 2341 individuals were screened, of whom 2307 eligible individuals were enrolled and vaccinated: 1107 (738 girls and 369 boys) in the cohort aged 9-14 years and 1200 (819 women and 381 men) in the cohort aged 15-26 years. No race or ethnicity data were collected. 350 girls and 349 boys in the SIIPL quadrivalent HPV vaccine group and 338 women in the comparator vaccine group were included in the modified per-protocol population for the primary endpoint analysis. The median follow-up for the analyses was 221 days (IQR 215-231) for girls and 222 days (217-230) for boys in the SIIPL quadrivalent HPV vaccine group, 223 days (216-232) for girls in the comparator vaccine group, and 222 days (216-230) for women in the comparator vaccine group. GMT ratios were non-inferior in girls and boys receiving the SIIPL quadrivalent HPV vaccine compared with women receiving the comparator vaccine: GMT ratios for girls were 1·97 (98·75% CI 1·67-2·32) for HPV type 6, 1·63 (1·38-1·91) for HPV type 11, 1·90 (1·60-2·25) for HPV type 16, and 2·16 (1·79-2·61) for HPV type 18. For boys the GMT ratios were 1·86 (1·57-2·21) for HPV type 6, 1·46 (1·23-1·73) for HPV type 11, 1·62 (1·36-1·94) for HPV type 16, and 1·80 (1·48-2·18) for HPV type 18. The safety population comprised all 1107 participants (369 girls and 369 boys in the SIIPL quadrivalent HPV vaccine group, and 369 girls in the comparator group). Solicited adverse events occurred in 176 (48%) of 369 girls and 124 (34%) of 369 boys in the SIIPL vaccine group and 179 (49%) of 369 girls in the comparator vaccine group. No grade 3-4 solicited adverse events occurred within 7 days of each dose. Unsolicited adverse events occurred in 143 (39%) girls and 147 (40%) boys in the SIIPL vaccine group, and 143 (39%) girls in the comparator vaccine group. The most common grade 3 unsolicited adverse event was dengue fever, in one (<1%) girl in the SIIPL vaccine group and three (1%) girls in the comparator group. There were no grade 4 or 5 adverse events. Serious adverse events occurred in three (1%) girls and three (1%) boys in the SIIPL vaccine group, and five (1%) girls in the comparator vaccine group. No vaccine-related serious adverse events were reported. There were no treatment-related deaths. INTERPRETATION: We observed a non-inferior immune response with the SIIPL quadrivalent HPV vaccine in girls and boys aged 9-14 years and an acceptable safety profile compared with the comparator vaccine. These findings support extrapolation of efficacy from the comparator vaccine to the SIIPL quadrivalent HPV vaccine in the younger population. The availability of the SIIPL quadrivalent HPV vaccine could help meet the global demand for HPV vaccines, and boost coverage for both girls and boys globally. FUNDING: Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.

Antibody Persistence Following Administration of a Hexavalent DTwP-IPV-HB-PRP~T Vaccine Versus Separate DTwP-HB-PRP~T and IPV Vaccines and Safety and Immunogenicity of a Booster Dose of DTwP-IPV-HB-PRP~T Administered With an MMR Vaccine in Healthy Infants in India.

BACKGROUND: Antibody persistence of a whole-cell pertussis-containing hexavalent vaccine (DTwP-IPV-HB-PRP~T) and its co- or sequential administration with measles, mumps, rubella (MMR) vaccine were evaluated. METHODS: Phase III, open-label, randomized, multicenter study in India. Healthy toddlers 12-24 months of age who had received DTwP-IPV-HB-PRP~T or separate DTwP-HB-PRP~T+IPV primary vaccination at 6-8, 10-12 and 14-16 weeks of age received a DTwP-IPV-HB-PRP~T booster concomitantly with MMR (N = 336) or 28 days before MMR (N = 340). Participants had received a first dose of measles vaccine. Immunogenicity assessment used validated assays and safety was by parental reports. All analyses were descriptive. RESULTS: All participants had prebooster anti-T ≥0.01 IU/mL and anti-polio 1 and 3 ≥8 1/dil, and ≥96.5% had anti-D ≥0.01 IU/mL, anti-HBs ≥10 mIU/mL, anti-polio 2 ≥8 1/dil and anti-PRP ≥0.15 µg/mL; for pertussis, antibody persistence was similar in each group. Postbooster immunogenicity for DTwP-IPV-HB-PRP~T was similar for each antigen in each group: ≥99.5% of participants had anti-D ≥0.01 IU/mL, anti-T ≥0.01 IU/mL, anti-polio 1, 2 and 3 >8 1/dil, anti-HBs ≥10 mIU/mL and anti-PRP ≥1 µg/mL; for pertussis, vaccine response was similar in each group [72.0%-75.9% (anti-PT), 80.8%-81.4% (anti-FIM), 77.6%-79.5% (anti-PRN), 78.2%-80.8% (anti-FHA)]. There was no difference in MMR immunogenicity between groups, and no difference in DTwP-IPV-HB-PRP~T booster immunogenicity based on the primary series. There were no safety concerns. CONCLUSIONS: DTwP-IPV-HB-PRP~T antibody persistence was similar to licensed comparators. Booster immunogenicity was robust after DTwP-IPV-HB-PRP~T with or without MMR, and MMR immunogenicity was not affected by coadministration with DTwP-IPV-HB-PRP~T. CLINICAL TRIALS REGISTRY INDIA NUMBER: CTRI/2020/04/024843.

Feasibility and acceptability of the paediatric pulse oximeter in integrated management of neonatal and childhood illnesses (IMNCI) services by public health facilities: A qualitative study in rural Western India.

Background: Pneumonia contributes to about 15% of child deaths globally, with 20% of the overall deaths occurring in India. Although WHO recommends the use of pulse oximeters (PO) in first-level facilities for early detection of child pneumonia in low- and middle-income countries (LMICs), this has not yet been implemented in India. We aimed to assess the feasibility and acceptability of introducing PO in integrated management of neonatal and childhood illnesses (IMNCI) services at primary health centres (PHC) in the rural Pune district. Methods: We identified medical officers (MO) and auxiliary nurse midwives (ANM) from six PHCs as study participants due to their involvement in the treatment of children. We developed in-depth interview (IDI) guides for both groups to explore their IMNCI knowledge and attitude towards the program through a qualitative study. We conducted interviews with MOs (n = 6) and ANMs (n = 6) from each PHC. The PO module was added to explore perceptions about its usefulness in diagnosing pneumonia. After baseline assessment, we conducted training sessions on adapted IMNCI services (including PO use) for MOs and ANMs. PO devices were provided at the study PHCs. Results: At baseline, no PO devices were being used at study PHCs; PHC staff demonstrated satisfactory knowledge about paediatric pneumonia management and demanded refresher IMNCI training. They also felt the need to reiterate the PO use for early diagnosis of pneumonia in children and highlighted the challenges encountered in managing pneumonia at PHCs, such as health system-related challenges and parents' attitudes towards care seeking. There was positive acceptance of training and PO started to be used immediately in PHCs. There was increased confidence in using PO at endline. PO use in examining symptomatic children increased from 26 to 85%. Conclusions: Paediatric PO implementation could be integrated successfully at PHC levels; we found pre-implementation training and provision of PO to PHCs to be helpful in achieving this goal. This intervention demonstrated that an algorithm to diagnose pneumonia in children that included PO could improve case management.

Safety and Protective Effects of Influenza Vaccination in Pregnant Women on Pregnancy and Birth Outcomes in Pune, India: A Cross-Sectional Study.

BACKGROUND: Maternal influenza vaccination provides effective protection against influenza infections in pregnant women and their newborns. In India, the influenza vaccine has not yet been offered through immunization programs, owing to the lack of sufficient safety data for pregnant Indian women. METHODS: This cross-sectional observational study enrolled 558 women admitted to the obstetrics ward of a civic hospital in Pune. Study-related information was obtained from the participants through hospital records and interviews using structured questionnaires. Univariate and multivariable analysis was used, and the chi-square test with adjusted odds ratio was estimated to account for vaccine exposure and the temporal nature of each outcome, respectively. RESULTS: Women not vaccinated against influenza during pregnancy had a higher risk of delivering very LBW infants, and possible protective effects were suggested (AOR 2.29, 95% CI 1.03 to 5.58, p = 0.03). No association was observed between maternal influenza vaccination for Caesarean section (LSCS) (AOR 0.97, 95% CI, 0.78, 1.85), stillbirth (AOR 1.8, 95% CI 0.18, 24.64) and NICU admission (AOR, 0.87, 0.29 to 2.85), and congenital anomaly (AOR, 0.81, 0.10 to 3.87). INTERPRETATION: These results show that the influenza vaccine administered during pregnancy is safe and might lower the risk of negative birth outcomes.

Effect of reduced two-dose (1+1) schedule of 10 and 13-valent pneumococcal conjugate vaccines (SynflorixTM and Prevenar13TM)) on nasopharyngeal carriage and serotype-specific immune response in the first two years of life: Results from an open-labelled randomized controlled trial in Indian children.

INTRODUCTION: This study aimed to assess the effect of a reduced dose regime (1 + 1) of PCV10 and PCV13 along with 3-dose regimes on pneumococcal vaccine-type (VT) carriage and immunogenicity in the first two years of life in PCV-naïve Indian children. METHODS: A total of 805 healthy infants aged 6-8 weeks were randomised to 7 groups (n = 115). Six groups received SynflorixTM(PCV10) or Prevenar13TM(PCV13) in the following schedules: 3 + 0 (three primary at 6, 10, and 14 weeks); 2 + 1 (two primary 6 and 14 weeks with booster at 9 months; 1 + 1 (one primary at 14 weeks with booster at 9 months). The 7th group was a PCV-naïve control group. Nasopharyngeal swabs were collected at 6, 18 weeks, 9, 10, 15, and 18 months of age. Venous blood samples were collected at 18 weeks, 9, 10, and 18 months of age for assessment of sero-specific IgG antibodies. Additionally, functional activity using a serotype specific opsonophagocytic assay (OPA) was assessed at 10 and 18 months of age in a subset (20%) of participants. RESULTS: All schedules of PCV13 showed significant 13VT carriage reduction in the second year of life as compared to control. At 15 months of age, PCV13 (1 + 1) showed 45 % reduction in 13VT-carriage compared to the control [OR = 0.55 (95% CI; 0.31-0.97), p= 0.038]. None of the PCV10 schedules showed significant reduction in 10VT carriage in the second year. Although not powered for these outcomes, at 18 months of age, 1 + 1 and 2 + 1 schedules of both vaccines demonstrated higher sero-responders for all serotypes, higher geometric mean concentrations (GMC) for all serotypes except 23F [with both vaccines], higher percent OPA responders and OPA geometric mean titres (GMT) compared to the 3 + 0 schedules for all serotypes. CONCLUSION: The reduced dose schedule (1 + 1) of PCV13 results in significant VT-carriage reduction in the second year of life. Immune protection provided by 1 + 1 schedules of PCV10 and PCV13 in the second year of life is comparable to WHO-recommended 3-dose schedules.

Safety and immunogenicity of an indigenously developed tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine (Tdap) in adults, adolescents, and children in India.

BACKGROUND: This study assessed safety and immunogenicity of Serum Institute of India Pvt Ltd (SIIPL)'s tetanus toxoid (TT), diphtheria toxoid (DT), and acellular pertussis booster vaccine (Tdap). RESEARCH DESIGN AND METHODS: In this Phase II/III, multicenter, randomized, active-controlled, open-label study, 1500 healthy individuals, aged 4-65 years, were randomized to receive a single dose of SIIPL Tdap or comparator Tdap vaccine (Boostrix®; GlaxoSmithKlines, India). Adverse events (AEs) during initial 30 minutes, 7-day, 30-day post-vaccination were assessed. Blood samples were taken before and 30 days post-vaccination for immunogenicity assessment. RESULTS: No significant differences in incidence of local and systemic solicited AEs were observed between the two groups; no vaccine-related serious AEs were reported. SIIPL Tdap was non-inferior to comparator Tdap in achieving booster responses to TT and DT in 75.2% and 70.8% of the participants, respectively, and to pertussis toxoid (PT), pertactin (PRN), and filamentous hemagglutinin (FHA) in 94.3%, 92.6%, and 95.0% of the participants, respectively. Anti-PT, anti-PRN, and anti-FHA antibody geometric mean titers in both the groups, were significantly higher post-vaccination compared to pre-vaccination. CONCLUSIONS: Booster vaccination with SIIPL Tdap was non-inferior to comparator Tdap with respect to immunogenicity against tetanus, diphtheria, and pertussis and was well tolerated.

Working as frontline health facilitators, service providers, program supporters, and social health activists in Indian hilly terrain areas: A qualitative study of accredited social health activists' experiences before and during the COVID-19 pandemic.

Background: Community health workers (CHW) contribute to achieving health targets of the Sustainable Development Goals (SDG) and Universal Health Care (UHC) in low- and middle-income countries (LMICs). In India, accredited social health activists (ASHAs) function as health facilitators, service providers, and programme supporters for rural and tribal communities and are at the frontline during the COVID-19 pandemic. We aimed to describe the ASHAs' work roles both before and during the COVID-19 pandemic, explore the tasks ASHAs performed throughout the pandemic, and understand its effects on the evolving role of ASHAs. Methods: We used qualitative data from a pre-COVID-19 study conducted in 2018-2019 including face-to-face interviews with purposively sampled ASHAs and their health care supervisors (n = 18) from rural Maharashtra state (India), and a follow-up study during the COVID-19 pandemic using telephonic interviews with a subset of participants from the pre-COVID-study (n = 8). Data were analysed thematically using MAXQDA v11.00. Results: The primary theme in the pre-COVID-19 study was ASHAs' role as described above, except as social health activists, linking beneficiaries to the local maternal and child health care services, distributing medicines for common illnesses, access to government schemes, and engaging in multiple health surveys. During the pandemic, raising awareness, screening of at-risk populations, arranging referrals, providing treatment and follow-up to COVID-19 patients, and supporting their family members. These activities increased the workload and health risks to ASHAs and their family, causing stress and tension among them. However, they had effectively carried out the new duties. ASHAs have improved their status, earning praise from families, society, and the government. They were honoured with the Global Health Leaders Award at the 75th World Health Assembly. Conclusion: ASHAs' contribution to the health system improved the indicators related to maternal and child health during the pre-COVID-19 pandemic. Additionally, they maintained frontline health care during the COVID-19 pandemic, demonstrating resilience despite the challenges of increased workload and stress. However, the COVID-19 pandemic highlights the need to respond to and understand the implications of ASHAs' evolving roles.

Changes in immunological parameters by ageing in rural healthy Indian adults and their associations with sex and lifestyle.

Several factors including sex and lifestyle have been reported to contribute to the age-related alteration of immune functions. The study was undertaken to determine age-related differences in the proportion of peripheral blood mononuclear lymphocytes in the Indian population using blood samples from 67 healthy adults (33 females and 34 males) aged between 20 and 80 years old. In the linear regression analysis to estimate the relationship with age categories, there was a significant increase in the frequency of natural killer cells with ageing, while their cytolytic activity significantly declined. The frequency of CD4+ T cells increased with age, whereas that of CD8+ T cells decreased, resulting in the age-associated increase of the CD4/CD8 ratio. The subsets of B cells did not show any significant relationship with age. Although there were variations between the male and female subgroups in effect size of ageing, the trends were in the same direction in all the parameters. Reduced fat intake was associated with a lower frequency of CD4+ T cells, and higher serum cotinine level was associated with a higher CD4/CD8 ratio. The results indicate that cellular immunity in the Indian population is affected by ageing, while humoral immunity is less susceptible to ageing.

Safety and immunogenicity of the Rotavac and Rotasiil rotavirus vaccines administered in an interchangeable dosing schedule among healthy Indian infants: a multicentre, open-label, randomised, controlled, phase 4, non-inferiority trial.

BACKGROUND: Rotavirus is the leading cause of severe dehydrating gastroenteritis among children younger than 5 years in low-income and middle-income countries. Two vaccines-Rotavac and Rotasiil-are used in routine immunisation in India. The safety and immunogenicity of these vaccines administered in a mixed regimen is not documented. We therefore aimed to compare the safety and seroresponse of recipients of a mixed regimen versus a single regimen. METHODS: We did a multicentre, open-label, randomised, controlled, phase 4, non-inferiority trial at two sites in India. We recruited healthy infants aged 6-8 weeks. Infants with systemic disorders, weight-for-height Z scores of less than minus three SDs, or a history of persistent diarrhoea were excluded. Eligible infants were randomly allocated to six groups in equal numbers to receive either the single vaccine regimen (ie, Rotavac-Rotavac-Rotavac [group 1] or Rotasiil-Rotasiil-Rotasiil [group 2]) or the mixed vaccine regimen (ie, Rotavac-Rotasiil-Rotavac [group 3], Rotasiil-Rotavac-Rotasiil [group 4], Rotavac-Rotasiil-Rotasiil [group 5], or Rotasiil-Rotavac-Rotavac [group 6]). Randomisation was done using an online software by site in blocks of at least 12. The primary outcome was seroresponse to rotavirus vaccine, measured using rotavirus-specific serum IgA antibodies 4 weeks after the third dose. The seroresponse rates were compared between recipients of the four mixed vaccine regimens (consisting of various combinations of Rotavac and Rotasiil) with recipients of the single vaccine regimens (consisting of Rotavac or Rotasiil only for all three doses). The non-inferiority margin was set at 10%. Safety follow-ups were done for the duration of study participation. This trial was registered with the Clinical Trials Registry India, number CTRI/2018/08/015317. FINDINGS: Between March 25, 2019, and Jan 15, 2020, a total of 1979 eligible infants were randomly assigned to receive a single vaccine regimen (n=659; 329 in group 1 and 330 in group 2) or a mixed vaccine regimen (n=1320; 329 each in groups 3 and 4, and 331 each in groups 5 and 6). All eligible participants received the first dose, 1925 (97·3%) of 1979 received the second dose, and 1894 (95·7%) received all three doses of vaccine. 1852 (93·6%) of 1979 participants completed the follow-up. The immunogenicity analysis consisted of 1839 infants (1238 [67·3%] in the mixed vaccine regimen and 601 [32·7%] in the single vaccine regimen; 13 samples were insufficient in quantity) who completed vaccination and provided post-vaccination sera. The seroresponse rate in the mixed vaccine regimen group (33·5% [95% CI 30·9-36·2]) was non-inferior compared with the single vaccine regimen group (29·6% [26·1-33·4]); the seroresponse rate difference was 3·9% (95% CI -0·7 to 8·3). The proportion of participants with any type of solicited adverse events was 90·9% (95% CI 88·4-93·0) in the single vaccine regimen group and 91·1% (89·5-92·6) in the mixed vaccine regimen group. No vaccine-related serious adverse events or intussusception were reported during the study. INTERPRETATION: Rotavac and Rotasiil can be safely used in an interchangeable manner for routine immunisation since the seroresponse was non-inferior in the mixed vaccine regimen compared with the single vaccine regimen. These results allow for flexibility in administering the vaccines, helping to overcome vaccine shortages and supply chain issues, and targeting migrant populations easily. FUNDING: Ministry of Health and Family Welfare, Government of India. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Efficacy of transdermal delivery of liposomal micronutrients through body oil massage on neurodevelopmental and micronutrient deficiency status in infants: results of a randomized placebo-controlled clinical trial.

BACKGROUND: Micronutrient deficiency is a known cause of adverse neurodevelopment and growth. Poor adherence to oral regimes of micronutrient supplements is a known challenge during the implementation of supplementation programs. The present study evaluates the benefits of liposomal encapsulated micronutrient fortified body oils (LMF oil) that can be used for infant body massage in terms of neurodevelopment and prevention of deficiency. STUDY DESIGN: Double-blind randomized clinical trial. METHODS: A total of 444 healthy infants aged 4-7 weeks were randomized to receive either LMF oil (containing iron, vitamin D, folate, and vitamin B12) or placebo oil for gentle body massage till 12 months of age. Blood samples were collected at 6 and 12 months for transferrin saturation (TSAT), hemoglobin, and 25-hydroxy vitamin (25-OH-D) levels. Mental and motor development was assessed at 12 months using developmental assessment for Indian Infants (DASII). RESULTS: A total of 391 infants completed the study. There was no significant improvement in the hemoglobin in the intervention group at 12 months of age as compared to the placebo group [- 0.50 vs.-0.54 g%]. There was a marginally significant improvement in 25-OH-D at 12 months in the LMF oil group [+ 1.46vs.-0.18 ng/ml, p = 0.049]. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age [adjusted mean change + 0.11vs.-0.51 g%, p = 0.043]. The mental or motor developmental quotients in the intervention group were not significantly different from those in the placebo group. CONCLUSION: Use of LMF oil for prevention of nutritional deficiency did not offer significant protection against nutritional anemia but prevented vitamin D deficiency to some extent with improvement in 25-OH-D at 12 months. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age. The intervention did not result in significant improvement in mental or motor development. Further evaluation with increased doses needs to be undertaken. TRIAL REGISTRATION: CTRI no: CTRI/2017/11/010710 ; dated 30/11/2017.

Nasopharyngeal pneumococcal carriage in South Asian infants: Results of observational cohort studies in vaccinated and unvaccinated populations.

BACKGROUND: Nasopharyngeal pneumococcal carriage (NPC) is a prerequisite for invasive pneumococcal disease and reduced carriage of vaccine serotypes is a marker for the protection offered by the pneumococcal conjugate vaccine (PCV). The present study reports NPC during the first year of life in a vaccinated (with PCV10) cohort in Bangladesh and an unvaccinated cohort in India. METHODS: A total of 450 and 459 infants were recruited from India and Bangladesh respectively within 0-7 days after birth. Nasopharyngeal swabs were collected at baseline, 18 and 36 weeks after birth. The swabs were processed for pneumococcal culture and identification of serotypes by the Quellung test and polymerase chain reaction (PCR). An identical protocol was applied at both sites. RESULTS: Prevalence of NPC was 48% in the Indian and 54.8% in the Bangladeshi cohort at 18 weeks. It increased to 53% and 64.8% respectively at 36 weeks. The average prevalence of vaccine serotypes was higher in the Indian cohort (17.8% vs 9.8% for PCV-10 and 26.1% vs17.6% for PCV-13) with 6A, 6B, 19F, 23F, and 19A as the common serotypes. On the other hand, the prevalence of non-vaccine serotypes was higher (43.6% vs 27.1% for non-PCV13) in the Bangladeshi cohort with 34, 15B, 17F, and 35B as the common serotypes. Overcrowding was associated with increased risk of pneumococcal carriage. The present PCV-13 vaccine would cover 28%-30% and 47%-48% serotypes in the Bangladeshi and Indian cohorts respectively. CONCLUSIONS: South Asian infants get colonised with pneumococci early in infancy; predominantly vaccine serotypes in PCV naïve population (India) and non-vaccine serotypes in the vaccinated population (Bangladesh). These local findings are important to inform the public health policy and the development of higher valent pneumococcal vaccines.

Conducting community-based pediatric research in rural India: Experience from vadu rural health program.

This paper describes unique challenges faced during conduct of community research studies in rural population of Maharashtra at Vadu Rural Health Program, Pune, India. Some of the ethical issues faced include difficulty in comprehending the informed consent by rural families with low education levels and ensuring adequate compensation for study participation without undue inducement, ensuring large number of recruitments during early infancy, ensuring adherence to intervention by care-providers, retention of participants especially in studies having long follow-ups and regulatory compliance for serious adverse event reports are major operational challenges. The delays faced in approvals from the Health Ministry Screening Committee and lack of specific regulatory guidance on community-based conduct of studies pose challenges in terms of study timelines and operational aspect of these studies. Provision of study-related information during prestudy visits, designing patient information sheets in simple language, involving the decision-making member of the family, adequate time for families for decision-making are certain measures that have been useful for effective informed consent administration. Collaboration with accredited social health activists and auxillary nurse midwives for line-listing of pregnancies and births and regular conduction of prestudy visits or community sensitization meetings have been useful for the recruitment of large number of study participants during infancy. Strategies such as provision of universal immunization, selection of field research assistants from the local population, regular home visits, and provision of medical care has been helpful in retention of the study participants. Networking with local health facilities and local government bodies has helped in the provision of medical care to the study participants and in the management of serious adverse events. Our experience can provide important learnings to other investigators from developing countries working in the domain of child health.

Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the "ProSPoNS" Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. DISCUSSION: This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low-middle-income countries. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019.

Acute respiratory distress syndrome (ARDS) as an adverse event following immunization: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration Case Definition of the term "Acute Respiratory Distress Syndrome - ARDS" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission. The comments of the reviewers were taken into consideration and edits incorporated in this final manuscript.

Interplaying role of healthcare activist and homemaker: a mixed-methods exploration of the workload of community health workers (Accredited Social Health Activists) in India.

BACKGROUND: Globally, community health workers (CHWs) are integral contributors to many health systems. In India, Accredited Social Health Activists (ASHAs) have been deployed since 2005. Engaged in multiple health care activities, they are a key link between the health system and population. ASHAs are expected to participate in new health programmes prompting interest in their current workload from the perspective of the health system, community and their family. METHODS: This mixed-methods design study was conducted in rural and tribal Primary Health Centers (PHCs), in Pune district, Western Maharashtra, India. All ASHAs affiliated with these PHCs were invited to participate in the quantitative study, those agreeing to contribute in-depth interviews (IDI) were enrolled in an additional qualitative study. Key informants' interviews were conducted with the Auxiliary Nurse Midwife (ANM), Block Facilitators (BFF) and Medical Officers (MO) of the same PHCs. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed thematically. RESULTS: We recruited 67 ASHAs from the two PHCs. ASHAs worked up to 20 h/week in their village of residence, serving populations of approximately 800-1200, embracing an increasing range of activities, despite a workload that contributed to feelings of being rushed and tiredness. They juggled household work, other paid jobs and their ASHA activities. Practical problems with travel added to time involved, especially in tribal areas where transport is lacking. Their sense of benefiting the community coupled with respect and recognition gained in village brought happiness and job satisfaction. They were willing to take on new tasks. ASHAs perceived themselves as 'voluntary community health workers' rather than as 'health activists". CONCLUSIONS: ASHAs were struggling to balance their significant ASHA work and domestic tasks. They were proud of their role as CHWs and willing to take on new activities. Strategies to recruit, train, skills enhancement, incentivise, and retain ASHAs, need to be prioritised. Evolving attitudes to the advantages/disadvantages of current voluntary status and role of ASHAs need to be understood and addressed if ASHAs are to be remain a key component in achieving universal health coverage in India.

Assessment of perceived distress due to nasopharyngeal swab collection in healthy Indian infants participating in a clinical trial.

Routinely children are exposed to various procedures as a part of clinical care and/or research participation. Public health strategies to contain current COVID-19 pandemic demanded massive nasopharyngeal swab testing but limited data exist to confirm the extent of the pain and distress that result from this procedure. These data could help clinicians to formulate mitigation strategies, influence public health directives, and inform review boards/ethics committees to decide on risk-benefit ratio of the procedure. Hence, an observational study to assess perceived distress was nested in a phase IV alternate and reduced dose schedule trial of the pneumococcal conjugate vaccine (PCV) in which nasopharyngeal swab (NPS) was used to collect nasopharyngeal secretions as part of the study procedure. Out of 805 infant participants enrolled in the main study, a total of 425 infants were enrolled and observed for procedural distress at 18 weeks and 10 months of age using the Face Leg Activity Cry and Consolability (FLACC) Scale. The FLACC score and duration of cry were recorded. The mean FLACC score changed substantially from preprocedural to procedure in both age groups (from 0.08 to 5.8 at 18 weeks and from 0.5 to 7.007 at 10 months. P = <.0001). The proportion of infants experiencing higher FLACC scores (7-10) indicating severe distress increased significantly from 22% (n = 95) at 18 weeks to 61% (n = 248) at 10 months (P < .0001). The mean duration of cry was significantly increased from 23.03 seconds at 18 weeks to 52.6 seconds at 10 months (P = .00). Nasopharyngeal swab collection produced substantial distress which increased with age. Adequate training of sample collectors and supporting parent engagement during procedure could help in reducing the distress.

Immunogenicity and lot-to-lot consistency of a ready to use liquid bovine-human reassortant pentavalent rotavirus vaccine (ROTASIIL - Liquid) in Indian infants.

BACKGROUND: A lyophilized bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, Rotasiil®) was licensed in 2016. A liquid formulation of this vaccine (LBRV-PV, Rotasiil - Liquid) was subsequently developed and was tested for non-inferiority to Rotasiil® and for lot-to-lot consistency. METHODS: This Phase II/III, open label, randomized study was conducted at seven sites across India from November 2017 to June 2018. Participants were randomized into four arms; Lots A, B, and C of LBRV-PV and Rotasiil® in 1:1:1:1 ratio. Three doses of study vaccines were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. Non-inferiority of LBRV-PV to Rotasiil was proven if the lower limit two-sided 95% confidence interval (CI) of geometric mean concentration (GMC) ratio was at least 0.5. Lot-to-lot consistency was proven if 95% CI of the GMC ratios of three lots were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: Of the 1500 randomized infants, 1436 infants completed the study. The IgA GMC ratio of LBRV-PV to Rotasiil® was 1.19 (95% CI 0.96, 1.48). The corresponding IgA seropositivity rates were 60.41% (57.41, 63.35) and 52.75% (47.48, 57.97). The IgA GMC ratios among the three LBRV-PV lots were: Lot A versus Lot B: 1.34 (1.03, 1.75); Lot A versus Lot C: 1.22 (0.93, 1.60); and Lot B versus Lot C: 0.91 (0.69, 1.19). The 95% CIs for the GMC ratios were between 0.69 and 1.75. The incidence of solicited reactions was comparable across the four arms. Only one serious adverse event of gastroenteritis event in the Rotasiil® group was causally related. CONCLUSION: The immunological non-inferiority of LBRV-PV against Rotasiil® as well as lot-to-lot consistency of LBRV-PV was demonstrated. LBRV-PV had safety profile similar to Rotasiil®. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov [NCT03474055] and Clinical Trial Registry of India [CTRI/2017/10/010104].