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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. 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. 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. 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. Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.

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. 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. 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. 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.

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.

Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia. We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18–45 years, children aged 24–59 months, older infants aged 9–12 months, and infants aged 6–8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267. 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67–190] to 208 U/mL [117–369]), children (201 U/mL [138–294] to 368 U/mL [234–580]), and older infants (179 U/mL [129–250] to 249 U/mL [130–477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33–94] to 63 U/mL [35–114] in adults, from 23 U/mL [15–34] to 51 U/mL [34–76] in children, and from 21 U/mL [14–31] to 22 U/mL [14–33] in older infants). Immune response in infants aged 6–8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16–28] vs 2·88 U/mL [1·95–4·25]), but not Pakistani (3·76 U/mL [2·77–5·08] vs 2·77 U/mL [2·1–3·66]), infants. Vi-CRM197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies. Vi-CRM197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO. Sclavo Vaccines Association and Regione Toscana.

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.

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.

BackgroundPneumonia 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.MethodsWe 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.ResultsAt 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%.ConclusionsPaediatric 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.

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.

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.

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. Nasopharyngeal swab collection in infants is distressful procedure. (a) The discomfort is more at 10 months of age as compared to 18 weeks. (b) It emphasizes the need for appropriate training, supports engagement of care takers, and use of alleviation measures. Findings of the study are important to pandemic context and could prompt the policy maker to think of pain/distress relieving measure to increase procedural compliance and public health behavior. These results could also help inform the review boards to decide on risk‐benefit ratio of the procedure while reviewing the trial protocols.