A Phase 3, randomized, non-inferiority study of a heterologous booster dose of SARS CoV-2 recombinant spike protein vaccine in adults.

Due to waning immunity following primary immunization with COVID-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines. In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with two doses of ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine (homologous booster of ChAdOx1 nCoV-19 or BBV152). Anti-S IgG and neutralizing antibodies (nAbs) were assessed at days 1, 29, and 181. Non-inferiority (NI) of SII-NVX-CoV2373 to the control vaccine was assessed based on the ratio of geometric mean ELISA units (GMEU) of anti-S IgG and geometric mean titers (GMT) of nAbs (NI margin > 0.67) as well as seroresponse (≥ 2 fold-rise in titers) (NI margin -10%) at day 29. Safety was assessed throughout the study period. In both the ChAdOx1 nCoV-19 prime and BBV152 prime cohorts, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 prime cohort, the GMEU ratio was 2.05 (95% CI 1.73, 2.43) and the GMT ratio was 1.89 (95% CI 1.55, 2.32) whereas the difference in the proportion of seroresponse was 49.32% (95% CI 36.49, 60.45) for anti-S IgG and 15% (95% CI 5.65, 25.05) for nAbs on day 29. In the BBV152 prime cohort, the GMEU ratio was 5.12 (95% CI 4.20, 6.24) and the GMT ratio was 4.80 (95% CI 3.76, 6.12) whereas the difference in the proportion of seroresponse was 74.08% (95% CI 63.24, 82.17) for anti-S IgG and 24.71% (95% CI 16.26, 34.62) for nAbs on day 29. The non-inferiority of SII-NVX-CoV2373 booster to the control vaccine for each prime cohort was met. SII-NVX-CoV2373 booster showed significantly higher immune responses than BBV152 homologous booster. On day 181, seroresponse rates were ≥ 70% in all the groups for both nAbs and anti-S IgG. Solicited adverse events reported were transient and mostly mild in severity in all the groups. No causally related SAE was reported. SII-NVX-CoV2373 as a heterologous booster induced non-inferior immune responses as compared to homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters. The vaccine was also safe and well tolerated.

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.

Determinants of maternal influenza vaccination in the context of low- and middle-income countries: A systematic review.

BACKGROUND: Pregnancy and early infancy are considered to be the vulnerable phases for severe influenza infection causing morbidity and mortality. Despite WHO recommendations, influenza is not included in the immunization programs of many low- and middle-income countries. This systematic review is aimed at identifying barriers and facilitators for maternal influenza vaccination amongst the perinatal women and their health care providers in low- and middle-income countries. METHODS: We selected 11 studies from the 1669 records identified from PubMed, CABI, EMBASE and Global Health databases. Studies related to both pandemic and routine influenza vaccination and studies conducted amongst women in the antenatal as well as postnatal period were included. Both qualitative, quantitative, cross-sectional and interventional studies were included. RESULTS: Knowledge about influenza disease, perception of the disease severity during pregnancy and risk to the foetus/newborn and perceived benefits of influenza vaccination during pregnancy were associated with increased uptake of influenza vaccination during pregnancy. Recommendation by health care provider, vaccination in previous pregnancy and availability of vaccine in public health system facilitated vaccine uptake. High parity, higher education, vaccination in the later months of pregnancy, less than 4 antenatal visits, concerns about vaccine safety and negative publicity in media were identified as barriers for influenza vaccination. Lack of government recommendation, concerns about safety and effectiveness and distrust in manufacturer were the barriers for the healthcare providers to recommend vaccination. CONCLUSION: While availability of influenza vaccine in public health system can be a key to the success of vaccine implementation program, increasing the awareness about need and benefits of maternal influenza vaccination amongst pregnant women as well as their health care providers is crucial to improve the acceptance of maternal influenza vaccination in low and middle-income countries.

Perceptions about controlled human infection model (CHIM) studies among members of ethics committees of Indian medical institutions: A qualitative exploration.

Introduction: Controlled Human Infection Model (CHIM) studies provide a unique platform for studying the pathophysiology of infectious diseases and accelerated testing of vaccines and drugs in controlled settings. However, ethical issues shroud them as the disease-causing pathogen is intentionally inoculated into healthy consenting volunteers, and effective treatment may or may not be available. We explored the perceptions of the members of institutional ethics committees (IECs) in India about CHIM studies. Methods: This qualitative exploratory study, conducted across seven sites in India, included 11 focused group discussions (FGD) and 31 in-depth interviews (IDI). A flexible approach was used with the aid of a topic guide. The data were thematically analyzed using grounded theory and an inductive approach. Emerging themes and sub-themes were analyzed, and major emergent themes were elucidated. Results: Seventy-two IEC members participated in the study including 21 basic medical scientists, 29 clinicians, 9 lay people, 6 legal experts and 7 social scientists. Three major themes emerged from this analysis-apprehensions about conduct of CHIM studies in India, a perceived need for CHIM studies in India and risk mitigation measures needed to protect research participants and minimize the associated risks. Conclusion: Development of a specific regulatory and ethical framework, training of research staff and ethics committee members, and ensuring specialized research infrastructure along with adequate community sensitization were considered essential before initiation of CHIM studies in India.

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.

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.

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.

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.

Feasibility of implementation of simplified management of young infants with possible serious bacterial infection when referral is not feasible in tribal areas of Pune district, Maharashtra, India.

INTRODUCTION: Neonatal infections are a common cause of death in India, but many families cannot access appropriate hospitals for its treatment due to various reasons. We implemented the World Health Organization PSBI management guideline when referral is not feasible within the public health system in Pune, India to evaluate feasibility, barriers and facilitators for its implementation. METHODS: A national-level consultative meeting between government officials and study partners resulted in a consensus on adaptation and implementation in four demonstration sites in selected states in India. At the state and district levels, similar meetings to plan the implementation strategy and roles were held between KEM Hospital Research Centre (KEMHRC) Pune and the public health system Pune, Maharashtra. The public health system was responsible for implementation of the intervention at eight tribal primary health centres (PHC) in Pune district, India, including delivering the intervention and ensuring supplies of all commodities while KEMHRC was responsible for technical support including training of health workers, assistance in PSBI identification and management, data collection and documentation of the implementation strategy. RESULTS: A total of 175 young infants with PSBI were identified and managed. Of these, 34 had critical illness (CI), 46 had clinical severe infection (CSI) and 10 were infants aged 0-6 days with fast breathing (FB) while 85 infants aged 7-59 days had fast breathing. Assuming a 10% incidence of PSBI among all live births, with 3071 live births recorded, the actual incidence of PSBI found in the study was 5.7%, resulting in an actual coverage was of 57%. Among the 90 infants with CI, CSI and FB in 0-6 days, who were advised referral to government tertiary care centre as per the PSBI guideline algorithm, 81 (90%) accepted referral while 9 (10%) refused and were offered treatment at primary health centres (PHC) with a seven-day course of injectable gentamicin and oral amoxicillin. All infants with FB in 7-59 days were offered treatment at PHCs as per the PSBI guideline algorithm with a seven-day course of oral amoxicillin. All except six infants who died and one with FB in 7-59 days, who was lost to follow-up, were successfully cured. Of the six who died, five had CSI and one had CI. Among the 81 infants with CI, CSI and FB in 0-6 days who accepted referral; 48(53%) were successfully referred to government tertiary facility while 33 (36.6%) preferred to visit a private tertiary health facility. The implementation strategy demonstrated a relatively high fidelity, acceptance and intervention penetration. Lack of training and confidence of the public health staff were major challenges faced, which were resolved to a large extent through supportive supervision and re-trainings. CONCLUSION: Management of PSBI is feasible to implement in out-patient facilities in the public health system, but technical support to the health system is required to jump-start the process. Fast breathing in 7-59 days old infants can be managed with oral amoxicillin without referral. A sustainable adoption of this intervention by the health system can lead to decrease in neonatal mortality and morbidity.

Development and Implementation of Liposomal Encapsulated Micronutrient Fortified Body Oil Intervention for Infant Massage: An Innovative Concept to Prevent Micronutrient Deficiencies in Children.

Indian communities have the ancient cultural practice of gentle oil massage for infants which has been shown to play a beneficial role in neuro-motor development. The concept of incorporating nanosized liposomes of micronutrients (i.e., iron, folate, vitamin B12, and vitamin D) in the body oil leverages this practice for transdermal supplementation of essential micro-nutrients. This paper describes the experience of developing an intervention in the form of body oil containing nanosized liposomes of iron and micro-nutrients built on the social context of infant oil massage using a theory of change approach. The process of development of the intervention has been covered into stages such as design, decide and implement. The design phase describes how the idea of nanosized liposomal encapsulated micronutrient fortified (LMF) body oil was conceptualized and how its feasibility was assessed through initial formative work in the community. The decide phase describes steps involved while scaling up technology from laboratory to community level. The implementation phase describes processes while implementing the intervention of LMF oil in a community-based randomized controlled study. Overall, the theory of change approach helps to outline the various intermediate steps and challenges while translating novel technologies for transdermal nutrient fortification to community level. In our experience, adaptation in the technology for large scale up, formative work and pilot testing of innovation at community level were important processes that helped in shaping the innovation. Meticulous mapping of these processes and experiences can be a useful guide for translating similar innovations.

Demographic surveillance over 12 years helps elicit determinants of low birth weights in India.

BACKGROUND: Low birth weight is an important predictor of maternal and child health. Birth weight is likely to be affected by maternal health, socioeconomic status and quality of health care facilities. OBJECTIVE: To assess trends in the birth weight, the proportion of low birth weight, maternal factors and health care facilities for delivery in villages of Western Maharashtra from the year 2004 to 2016 and to analyze factors associated with low birth weight for total birth data of 2004-2016. METHODS: Data collected for 19244 births from 22 villages in Vadu Health and Demographic Surveillance System (HDSS), Pune, Maharashtra, India from the year 2004 to 2016 were used for this analysis. RESULTS: There was an overall increase in the annual mean birth weight from 2640.12 gram [95% CI 2602.21-2686.84] in the year 2004 to 2781.19 gram [95% CI 2749.49-2797.95] in the year 2016. There was no secular trend to show increase or decrease in the proportion of low weight at birth. Increasing maternal age (>18 years) compounded with better education, reduced parity and increasing number of institutional deliveries were significant trends observed during the past decade. Low birth weight was found to be associated with female gender, first birth order, poor maternal education and occupation as cultivation. CONCLUSION: Changes in maternal age, education, occupation, and increased institutionalized deliveries contributed in to increasing birth weights in rural Maharashtra. Female gender, first birth order, poor maternal education and occupation of cultivation are associated with increased risk of low birth weight.

Delayed vaccination and its predictors among children under 2 years in India: Insights from the national family health survey-4.

OBJECTIVE: Delayed vaccination increases the susceptibility window for vaccine preventable diseases. Our analysis estimates the proportion of children between 10 and 23 months of age with delayed vaccination in India and the associated socio-demographic, maternal and child related factors. METHODS: We used individual level data from the National Family and Health Survey 4, conducted in 2015-2016. The primary outcome of the study was delayed vaccination for BCG, DPT- 1st dose and Measles. Delayed vaccination for each vaccine was defined as administration of the vaccine dose after 28 days of the minimum recommended age, as per the national immunization schedule in India. We estimated the proportion of children with delayed vaccination for each vaccine and used multivariable logistic regression to explore associated factors. FINDINGS: In the current analysis, 23.1%, 29.3% and 34.8% of children aged 10 to 23 months had delayed vaccination for BCG, DPT-1st dose and Measles respectively. Children from Muslim families (aOR 1.36 for BCG; aOR 1.45 for DPT-1; aOR 1.26 for Measles); birth weight < 2000 g (aOR 2.33 for BCG; aOR 1.53 for DPT-1; aOR 1.36 for Measles) had higher odds of delayed vaccination. Lower maternal education and belonging to a family from lower wealth quintile had higher odds of delayed vaccination. Children of mothers who had tetanus toxoid immunization during pregnancy had lower odds of delayed vaccination (aOR 0.69 for BCG; aOR 0.76 for DPT-1; aOR 0.78 for Measles). CONCLUSION: The proportion of children with delayed vaccination is high in India. Vaccine timeliness should be a core indicator of the immunization program with greater focus on groups with higher chances of delayed vaccination i.e. home birth, low birth weight new-borns, poorer households, children of mothers with lower education and children from Muslim families.

Facilitators and barriers for use of rotavirus vaccine amongst various stakeholders and its implications for Indian context - A systematic review.

Background: We performed a systematic review to evaluate factors affecting uptake of rotavirus vaccine amongst physicians, parents and health system. Methods: We identified 15 studies that met the inclusion criteria from 790 screened studies published between Jan 2005 to Jan 2016. Results: Perceived severity of rotavirus disease, efficacy of vaccine and recommendation by health authorities positively influenced uptake of vaccine amongst health care providers. Routine and timely vaccination with routine vaccines and availability of rotavirus vaccine in public health programme facilitated uptake. Family income, parental education and employment status positively influenced the decision to vaccinate by parents. Concerns about safety, high cost, additional workload and logistic problems in acquiring vaccine stocks were perceived as barriers. Conclusion: Improved awareness regarding the rotavirus vaccination amongst public and scientific community and strengthening of public health system for better and timely immunisation coverage are important factors to maximize uptake of rotavirus vaccine in India.

Reporting of adverse events for marketed drugs: Need for strengthening safety database.

Pharmacovigilance is an evolving discipline in the Indian context. However, there is limited regulatory guidance for adverse event reporting outside the purview of clinical trials. There are number of deficiencies in the framework for adverse event reporting from the perspective of pharma industry, health-care professional and general public due to which adverse events for marketed drugs are highly underreported. This article discusses the need to strengthen national safety database by promoting and mandating reporting of adverse events by all the stakeholders.