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Summary Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. Methods We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov , NCT04471519 . Findings Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group. Interpretation In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. Funding Bharat Biotech International. Translation For the Hindi translation of the abstract see Supplementary Materials section.

BACKGROUND: The first national severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey in India, done in May-June, 2020, among adults aged 18 years or older from 21 states, found a SARS-CoV-2 IgG antibody seroprevalence of 0·73% (95% CI 0·34-1·13). We aimed to assess the more recent nationwide seroprevalence in the general population in India. METHODS: We did a second household serosurvey among individuals aged 10 years or older in the same 700 villages or wards within 70 districts in India that were included in the first serosurvey. Individuals aged younger than 10 years and households that did not respond at the time of survey were excluded. Participants were interviewed to collect information on sociodemographics, symptoms suggestive of COVID-19, exposure history to laboratory-confirmed COVID-19 cases, and history of COVID-19 illness. 3-5 mL of venous blood was collected from each participant and blood samples were tested using the Abbott SARS-CoV-2 IgG assay. Seroprevalence was estimated after applying the sampling weights and adjusting for clustering and assay characteristics. We randomly selected one adult serum sample from each household to compare the seroprevalence among adults between the two serosurveys. FINDINGS: Between Aug 18 and Sept 20, 2020, we enrolled and collected serum samples from 29 082 individuals from 15 613 households. The weighted and adjusted seroprevalence of SARS-CoV-2 IgG antibodies in individuals aged 10 years or older was 6·6% (95% CI 5·8-7·4). Among 15 084 randomly selected adults (one per household), the weighted and adjusted seroprevalence was 7·1% (6·2-8·2). Seroprevalence was similar across age groups, sexes, and occupations. Seroprevalence was highest in urban slum areas followed by urban non-slum and rural areas. We estimated a cumulative 74·3 million infections in the country by Aug 18, 2020, with 26-32 infections for every reported COVID-19 case. INTERPRETATION: Approximately one in 15 individuals aged 10 years or older in India had SARS-CoV-2 infection by Aug 18, 2020. The adult seroprevalence increased approximately tenfold between May and August, 2020. Lower infection-to-case ratio in August than in May reflects a substantial increase in testing across the country. FUNDING: Indian Council of Medical Research.

Background Recently World Health Organization’s Global Task Force on Cholera Control (GTFCC) has published a global roadmap for prevention and control of cholera. We review preparedness of existing governmental non-vaccine programs and strategies for cholera prevention and control in India. We also describe strengths and gaps in the context of implementation of the global roadmap. Methods We reviewed published literature on non-vaccine based strategies for prevention and control of cholera in India and analyzed strengths and weaknesses of Government of India’s major anti-cholera and ante-diarrhea initiatives under Integrated Disease Surveillance Program (IDSP), National Rural Health Mission (NRHM), and other disease surveillance platforms. Results The first strategy of the WHO global roadmap, namely, preparedness for early detection and outbreak containment, has been addressed by the IDSP. NRHM complements IDSP activities by focusing on sanitation, hygiene, nutrition, and safe drinking water. We identified the need to adopt stricter case definitions and data validation protocols. Multi-sectoral approach to prevent cholera occurrences and re-occurrences [the second suggested strategy in the global roadmap], highlights identification of hotspots and implementing strategies based on transmission dynamics. We recommend development of comprehensive models by integrating data sources beyond the national programs to eliminate cholera hotspots in India. Implementing the third proposed strategy in the global roadmap, coordinated technical support, resource mobilization, and partnerships at local and global levels, has major challenges in India due to structural issues related to health systems and health programs. Conclusion Even with a robust public health infrastructure, absence of a national cholera program might have resulted in lack of specific focus and concerted efforts for cholera prevention and control in India. A National Taskforce for Cholera Control must develop India-specific ‘National Cholera Prevention and Response Road Map’ with an appropriate administrative and financially viable framework for its implementation.

Development of oral cholera vaccines (OCVs) experienced exciting times over the last two decades. A two-dose OCV, found efficacious through field trials, has obtained license for use in India. However, the current policy discussion revolves around 'to use or not to use' this vaccine covering entire population in the country, which has its own cost implications. We conducted a systematic review to address this conundrum. The disease burden and distribution, potential impact, programmatic issues, and competing priorities were kept in consideration. Peer reviewed articles and 'Integrated Disease Surveillance Program' data, generated by Government of India, were accessed. Our synthesis highlights that cholera burden estimates for India have been hamstrung by their extrapolation from a single incidence study conducted in Kolkata. Heterogeneity of 685 Indian districts regarding vulnerability to cholera is also obvious. Analysis of outbreak reports indicated that some settlements and sub-populations were more vulnerable to diarrhea/cholera than others. Infrastructure failure leading to contamination of drinking water and behavioral issues were of concern. Investment in safe water, sanitation and hygiene (WASH) and addressing inequity of health services pertaining to vulnerable population groups are the needs of the hour. OCV could play an important role as one of the elements in such multi-component cholera prevention effort. OCV administration through public health system in Odisha identified logistic challenges, with low uptake of the second dose at 46%, while 61% of the target population received the first dose. We identified accumulating global evidence on the advantage and efficacy of single-dose based approach, where the same OCV, as licensed in India, was used. The short-lasting nature of cholera outbreaks in India also argue in favor of such pragmatism. Failure to implement multi-component prevention strategy today runs the risk of perpetuating inequity, recurring cholera outbreaks in future, and its retinue of costs.

Background Group-A human rotaviruses (GARV) are among the major cause of childhood diarrhea worldwide. In lieu of monitoring the circulatory GARV strains and underscoring the burden of GARV related hospitalization, a systematic surveillance was conducted in three hospitals of eastern India. In this hospital-based diarrheal disease surveillance (2014–2016), GARV was the most common cause of acute infantile gastroenteritis. The strains were genotyped and characterized to understand their prevalence and phylodynamics prior to the introduction of vaccine in eastern India. Materials and methods A total of 3652 stool samples were screened from children (≤5 years) hospitalized with acute diarrhea during 2014–2016. Initial screening for VP6 antigen was done by ELISA. GARV positive samples were genotyped by multiplex semi-nested PCR and DNA sequencing and phylogenetic analyses were based on the capsid proteins VP4 and VP7. Results Of 3652 samples, 1817 (49.8%) were GARV positive. G1, G2, G3 and G9 in conjunction with P[4], P[6]and P[8]genotypes were seen to co-circulate in the population. A sharp deflection from G1 to G3 occurred since 2016; upsurge of G9 strains was seen in alternate years, whereas G2 strains had a low frequency. All the circulating genotypes depicted a low phylogenetic relatedness to the vaccine strains. Differences in antigenic epitopes of VP4 and VP7 proteins in local strains were seen when compared to the vaccine strains. A significant difference in the degree of dehydration, duration of mean hospital stay and frequency of vomiting/24 h between GARV positive and negative children was evident. Conclusion The study provides a relevant set of base-line data on high burden of rotaviral gastroenteritis and the varied genotypic diversity among children prior to the introduction of GARV vaccine in this endemic region. Continuous monitoring during post-vaccination era will be required to assess the impact of vaccination in this region.

Summary Background To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel). Methods We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18–55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519). Findings Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5–26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8–30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1–22·7) in the 6 μg with Algel group, and ten (10%; 6·9–23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4+ and CD8+ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups. Interpretation BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted. Funding Bharat Biotech International.

Background: Repeated cross-sectional serosurveys in the same geographic area establish the trend of the evolving pandemic. We present the findings of the third round of a national serosurvey to estimate the seroprevalence of SARS-CoV-2 infection among the general population and health care workers of India. Methods: We conducted the third population-based serosurvey between Dec 18, 2020 and Jan 6, 2021 in the same 700 villages or wards from 70 districts in 21 states across India, which were selected for the first and second serosurveys. We enrolled from each district, at least 400 individuals aged ≥ 10 years from general population and 100 HCWs from sub-district level public health facilities. Serum samples from general population were tested for the presence of IgG antibodies against nucleocapsid (N) and spike protein (S1-RBD) of SARS-CoV-2 using the Abbott and Siemens assays respectively, whereas sera from HCWs were tested for anti-S1-RBD. For general population, sera positive for either of the antibodies were considered positive, while sera positive for anti-S1-RBD were considered as positive for HCW. Weighted seroprevalence estimates were adjusted for sensitivity and specificity of respective assays. Findings: Of the 28,598 sera from general population, 4585 (16%) had IgG antibodies against N, 6647 (23.2%) against S1-RBD and 7436 (26%) against either. The weighted and assay characteristic adjusted seroprevalence against either of the antibodies was 24.1 (95%CI: 23.0% to 25.3%). Seroprevalence was lower in rural areas (21.4%, 95% CI: 20.3% to 22.6%) compared to urban non-slum (29.4%, 95% CI: 26.9% - 32.1%) and slum areas (34.6%, 95% CI: 31.0% to 38.3%). Among 7385 HCWs, the seroprevalence of anti-S1-RBD IgG antibodies was 25.6% (95% CI: 23.5% to 27.8%). Interpretation: Nearly one in four individuals aged 10 years or older from general population as well as HCWs were exposed to SARS-CoV-2 by December 2020 amounting to 271 million infections in India. Funding Statement: Indian Council of Medical Research Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare no competing interests Ethics Approval Statement: The project was approved by Institutional Human Ethics Committee at ICMR-National Institute of Epidemiology.

Background: ChAdOx1 nCoV-19 Corona Virus Vaccine (Recombinant) (SII-ChAdOx1 nCoV-19), manufactured in India at Serum Institute of India Pvt Ltd (SIIPL) after technology transfer from AstraZeneca, was evaluated in this phase 2/3 immunobridging study. Methods: This observer-blind study randomised participants 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (ChAdOx1 nCoV-19) (immunogenicity/reactogenicity cohort) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort). Two doses of vaccine (5 × 10¹⁰ viral particles) or placebo were given at 4-week intervals (+2-week window). Primary objectives were to demonstrate non-inferiority of SII-ChAdOx1 nCoV-19 to AZD1222 in terms of geometric mean titre (GMT) ratio of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibodies 28 days after second dose (defined as lower 95% CI >0·67) and to determine the incidence of serious adverse events (SAEs) causally related to SII-ChAdOx1 nCoV-19. Anti-spike IgG response was assessed using a validated multiplexed electrochemiluminescence-based immunoassay. Safety follow-up continued until 6 months after first dose. Findings: Between August 25 and October 31, 2020, n=1601 participants were enrolled: n=401 to the immunogenicity/reactogenicity cohort and n=1200 to the safety cohort. After two doses of SII-ChAdOx1 nCoV-19 or AZD1222, seroconversion rates for anti-spike IgG antibodies were 98·0% and 98·9%, respectively, with anti-spike IgG GMTs of 30 245·6 AU/mL (95% CI 26 794·0–34 141·8) and 28 558·3 AU/mL (23 479·3–34 735·8); SII-ChAdOx1 nCoV-19 was non-inferior to AZD1222 (GMT ratio 0·98; 95% CI 0·79–1·23). SAEs were reported in 15/1200 (1·3%, 95% CI 0·7–2·1), 2/300 (0·7%, 0·1–2·4) and 2/100 (2·0%, 0·2–7·0) participants who received SII-ChAdOx1 nCoV-19, placebo and AZD1222, respectively; none were causally related. SARS-CoV-2 infections were observed in 1·9% (n=22), 3·4% (n=10) and 2·0% (n=2) of the SII-ChAdOx1 nCoV-19, placebo and AZD1222 groups, respectively; none were severe. Interpretation: SII-ChAdOx1 nCoV-19 has a non-inferior immune response compared to AZD1222 and an acceptable safety/reactogenicity profile. Trial Registration: This study was registered with number CTRI/2020/08/027170 Funding: SIIPL, Indian Council of Medical Research, AstraZeneca. Declaration of Interest: PSK, CB, AD, MG, US, DK, and BG are employees of SIIPL. JV and EJK are employees of AstraZeneca. All other authors declare no competing interests. Ethical Approval: The study was approved by the Drugs Controller General of India (DCGI) and the ethics committees of each study site.

Background: India has the second highest number of COVID-19 cases. We evaluated the progression of the pandemic across the lockdowns and phased reopening during the first wave in India at the district level. Methods: More than 100 million COVID-19 test results along with other parameters available in the Indian Council of Medical Research (ICMR) database during March-October, 2020, was used for the analysis. District was chosen as the unit of analysis, as it is the smallest unit of administration in India. The districts were stratified as high, moderate, and low case load districts, and data analysis was done for each phase of lockdown. Findings: Of the 110.5 million tests included in the analysis, 54.79 million tests were performed using molecular methods, 53.58 million by rapid antigen tests (RATs) and 2.13 million by the indigenous TruNat platform. Only 7.95 million (7.16%) tests were among symptomatic individuals. The positivity proportion among symptomatic individuals (22.6%) was significantly higher than asymptomatic individuals (8.6%). The tests conducted, and positivity proportions were significantly higher in high caseload districts and 58% of these tests were by molecular methods as opposed to only one-third in low case load districts. The proportion of ‘symptomatic contacts’ being tested increased significantly around the peak. Interpretation: Laboratory parameters, along with other demographic information, can help us better understand the spread of the pandemic in a country. Such information can be crucial to formulate and implement public health policies in any future waves of the pandemic. Funding: Indian Council of Medical Research (ICMR) Declaration of Interest: We declare no competing interests Ethical Approval: Approval from the ICMR Central Ethics Committee on Human Research (Ref. No. NCDIR/BEU/ICMR-CECHR/75/2020) was obtained for this study and no patient identifiers were accessed during analysis or reporting.

Background: India witnessed a severe second wave of COVID-19 during March and June 2021. We did the fourth nationwide serosurvey to estimate prevalence of SARS-CoV-2 antibodies in the general population aged >=6 years and health care workers (HCWs). Methods: We did a cross-sectional study between 14 June and 6 July 2021 in 700 clusters in the same 70 districts across 21 states/Union Territory. From each district, a minimum of 400 individuals aged >=6 years from general population and 100 HCWs from the district public health facilities were included. The serum samples were tested for the presence of IgG antibodies against S1-RBD and nucleocapsid protein of SARS-CoV-2 using chemiluminescence immunoassay. We estimated the weighted and test adjusted seroprevalence of IgG antibodies against S1-RBD and/or nucleocapsid protein along with 95% CI. Findings: Of the 28,975 sera tested, the weighted and test adjusted prevalence of IgG antibodies against S1-RBD and/or nucleocapsid protein among the general population aged >=6 years was 67.6% (95% CI: 66.4 – 68.7). The seroprevalence increased with age and was not different in rural and urban areas. Compared to unvaccinated adults (62.3%, 95% CI: 60.9 – 63.7), seroprevalence was significantly higher among individuals who received one (81.0%, 95% CI: 79.6 - 82.3) and two doses (89.8%, 95% CI: 88.4 - 91.1). The seroprevalence of IgG antibodies among 7,252 health care workers was 85.2% (95% CI: 83.5 - 86.7). Interpretation: Nearly one third of the population is still seronegative. It is necessary to accelerate the coverage of COVID-19 vaccination among adults and continue adherence to non-pharmaceutical interventions. Funding: Indian Council of Medical Research. Declaration of Interest: None to declare. Ethical Approval: The Institutional Human Ethics Committee of the ICMR National Institute of Epidemiology, Chennai approved the study protocol.

Background: The first round of national serosurvey in India was conducted in May-June 2020 among adults from 21 States. The second serosurvey was conducted in August-September 2020 to estimate the nationwide seroprevalence for SARS-CoV-2 infection in the general population aged ten years and above. Methods: The household serosurvey was conducted among individuals aged ten years and above in the same 700 villages and wards from 70 districts selected during the first serosurvey. Blood samples were tested using the Abbott SARS-CoV-2 IgG assay. Seroprevalence was estimated after applying the sampling weights and adjusting for clustering and assay characteristics. In order to compare the adult seroprevalence between the two surveys, we randomly selected one adult serum sample from each household. Findings: The weighted and adjusted prevalence of infection among 29,082 individuals aged ten years and above was 6·6% (95% CI: 5·8% - 7·4%). The seroprevalence among adults was 7·1% (95% CI: 6·2% – 8·2%). Seroprevalence was similar across age groups, sex, and occupation. Seroprevalence was highest in urban slum areas followed by urban non-slum and rural areas. We estimated a cumulative 74·3 million infections in the country, with 26 – 32 infections for every reported COVID-19 case by August 2020. Interpretation: Nearly one in 15 individuals aged ten years and above had SARS-CoV-2 infection by August 2020. The adult seroprevalence increased ten times between May and August 2020. Lower infection to case ratio in August compared to May reflects a substantial increase in testing across the country. Funding: The study was funded by the Indian Council of Medical Research, New Delhi, India. The study sponsor was involved in reviewing the study design, writing of the manuscript and the decision to submit the paper for publication. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The authors obtained written informed consent from individuals aged 18 years and older. We obtained assent from children aged between 10–17 years, and written informed consent from their parents or guardians prior to the survey. The Central Ethics Committee of Health Research of Indian Council of Medical Research and the Institutional Human Ethics Committee of ICMR-National Institute of Epidemiology, Chennai approved the study protocol.

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a Toll-Like Receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or 6 μg with alum (Algel). Methods: We conducted a double-blind, randomised, multicentre, controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 healthy adults Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation were randomised equally to receive three vaccine formulations (n=100 each) prepared with 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel, and an Algel only control arm (n=75). Two intramuscular doses of vaccines were administered (twoweeks apart). Primary outcomes were reactogenicity and safety. Secondary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. Findings: Among 827 participants screened between July 13 and July 30, 2020, 375 participants were randomised. After both doses, the proportion (95%CI) of solicited local and systemic adverse reactions were 17% (10·5, 26·1), 21% (13·8, 30·5), 14% (8·1, 22·7), and 10% (6·9, 23·6) in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, 6 μg with Algel, and control groups, respectively . The most common solicited adverse events were injection site pain, headache, and fatigue. All solicited adverse events were mild (43, 69·3%) or moderate (19, 30·7%) and were more frequent after the first dose. One serious adverse event was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with AlgelIMDG, 6 μg with Algel-IMDG and 6 μg with Algel groups, respectively. CD4 + and CD8 + T cell responses were detected in a subset from both Algel-IMDG groups. Interpretations: BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted. Trial Registration Number: Clinicaltrials.gov : NCT04471519 Funding: This work was supported and funded by Bharat Biotech International Limited. Conflict of Interest: This work was supported and funded by Bharat Biotech International Limited. All authors are employees of one of the above-mentioned organisations, with no stock options or incentives. Co-author- K.E is the Chairman and Managing Director of Bharat Biotech. Ethical Approval: The trial was conducted across 11 sites in 9 states in India. The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees and was conducted in compliance with all International Council for Harmonization 114 (ICH) Good Clinical Practice guidelines.

Background This phase 2/3 immunobridging study evaluated the safety and immunogenicity of the ChAdOx1 nCoV-19 Coronavirus Vaccine (Recombinant) (SII-ChAdOx1 nCoV-19), manufactured in India at the Serum Institute of India Pvt Ltd (SIIPL), following technology transfer from the AstraZeneca. Methods This participant-blind, observer-blind study randomised participants 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (ChAdOx1 nCoV-19) (immunogenicity/reactogenicity cohort) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort). The study participants were enrolled from 14 hospitals across India between August 25 and October 31, 2020. Two doses of study products were given 4 weeks apart. The primary objectives were to demonstrate non-inferiority of SII-ChAdOx1 nCoV-19 to AZD1222 in terms of geometric mean titre (GMT) ratio of anti-SARS-CoV-2 spike IgG antibodies 28 days after the second dose (defined as lower limit of 95% CI >0·67) and to determine the incidence of serious adverse events (SAEs) causally related to SII-ChAdOx1 nCoV-19. The anti-spike IgG response was assessed using a multiplexed electrochemiluminescence-based immunoassay. Safety follow-up continued until 6 months after first dose. Trial registration: CTRI/2020/08/027170. Findings 1601 participants were enrolled: 401 to the immunogenicity/reactogenicity cohort and 1200 to the safety cohort. After two doses, seroconversion rates for anti-spike IgG antibodies were more than 98·0% in both the groups. SII-ChAdOx1 nCoV-19 was non-inferior to AZD1222 (GMT ratio 0·98; 95% CI 0·78–1·23). SAEs were reported in ≤ 2·0% participants across the three groups; none were causally related. A total of 34 SARS-CoV-2 infections were reported; of which 6 occurred more than 2 weeks after the second dose; none were severe. Interpretation SII-ChAdOx1 nCoV-19 has a non-inferior immune response compared to AZD1222 and an acceptable safety/reactogenicity profile. Pharmacovigilance should be maintained to detect any safety signals. Funding SIIPL funded the contract research organisation and laboratory costs, while the site costs were funded by the Indian Council of Medical Research. The study vaccines were supplied by SIIPL and AstraZeneca.

Summary The availability of a safe and effective vaccine would be the eventual measure to deal with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) threat. Here, we have assessed the immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidates BBV152A, BBV152B, and BBV152C in Syrian hamsters. Three dose vaccination regimes with vaccine candidates induced significant titers of SARS-CoV-2-specific IgG and neutralizing antibodies. BBV152A and BBV152B vaccine candidates remarkably generated a quick and robust immune response. Post-SARS-CoV-2 infection, vaccinated hamsters did not show any histopathological changes in the lungs. The protection of the hamster was evident by the rapid clearance of the virus from lower respiratory tract, reduced virus load in upper respiratory tract, absence of lung pathology, and robust humoral immune response. These findings confirm the immunogenic potential of the vaccine candidates and further protection of hamsters challenged with SARS-CoV-2. Of the three candidates, BBV152A showed the better response., Graphical Abstract, Highlights • Vaccine candidates, BBV152 induced potent humoral immune response in Syrian hamsters • Early viral clearance from lower respiratory tract in vaccinated hamsters • BBV152 vaccine candidates protected Syrian hamsters from pneumonia, Biological Sciences; Immunity; Immunology; Viral Microbiology; Virology

The debate on the relevance of rotavirus vaccine to immunization program in India, where 27 million children are born every year, rages on. We synthesized the issues raised during these debates and reviewed the current literature to identify themes that could inform public health policy decision. The paradigm we used integrated disease burden data, host and environmental factors, vaccine efficacy, immunization program issues, and economic considerations. Our synthesis reveals that substantive country specific information on disease burden and economic impact of rotavirus illness in India is constrained by lack of public discussion and qualitative studies on mothers’ perceptions of the vaccine in concern. The need to improve the performance of current immunization program against six major vaccine preventable diseases (tuberculosis, diphtheria, tetanus, pertussis, polio, and measles) is often cited as a priority over introduction of rotavirus vaccine. Health in India being a state subject, we emphasize that the states which are in a position to reap the benefit of rotavirus vaccine, due to their good immunization program performance, should not be restrained from doing so. Meanwhile, the poorly performing states should step up their vaccination program and increase immunization coverage. Scientific, ethical and societal concerns captured through multiple sources indicate that the introduction of rotavirus vaccine would be a good investment for India.

Amphetamine type stimulants (ATS) have become the focus of increasing attention worldwide. There are understandable concerns over potential harms including the transmission of HIV. However, there have been no previous global reviews of the extent to which these drugs are injected or levels of HIV among users. A comprehensive search of the international peer-reviewed and grey literature was undertaken. Multiple electronic databases were searched and documents and datasets were provided by UN agencies and key experts from around the world in response to requests for information on the epidemiology of use. Amphetamine or methamphetamine (meth/amphetamine, M/A) use was documented in 110 countries, and injection in 60 of those. Use may be more prevalent in East and South East Asia, North America, South Africa, New Zealand, Australia and a number of European countries. In countries where the crystalline form is available, evidence suggests users are more likely to smoke or inject the drug; in such countries, higher levels of dependence may be occurring. Equivocal evidence exists as to whether people who inject M/A are at differing risk of HIV infection than other drug injectors; few countries document HIV prevalence/incidence among M/A injectors. High risk sexual behaviour among M/A users may contribute to increased risk of HIV infection, but available evidence is not sufficient to determine if the association is causal. A range of possible responses to M/A use and harm are discussed, ranging from supply and precursor control, to demand and harm reduction. Evidence suggests that complex issues surround M/A, requiring novel and sophisticated approaches, which have not yet been met with sufficient investment of time or resources to address them. Significant levels of M/A in many countries require a response to reduce harms that in many cases remain poorly understood. More active models of engagement with M/A users and provision of services that meet their specific needs are required.

Summary Background Injecting drug use is an increasingly important cause of HIV transmission in most countries worldwide. Our aim was to determine the prevalence of injecting drug use among individuals aged 15–64 years, and of HIV among people who inject drugs. Methods We did a systematic search of peer-reviewed (Medline, EmBase, and PubMed/BioMed Central), internet, and grey literature databases; and data requests were made to UN agencies and international experts. 11 022 documents were reviewed, graded, and catalogued by the Reference Group to the UN on HIV and Injecting Drug Use. Findings Injecting drug use was identified in 148 countries; data for the extent of injecting drug use was absent for many countries in Africa, the Middle East, and Latin America. The presence of HIV infection among injectors had been reported in 120 of these countries. Prevalence estimates of injecting drug use could be ascertained for 61 countries, containing 77% of the world's total population aged 15–64 years. Extrapolated estimates suggest that 15·9 million (range 11·0–21·2 million) people might inject drugs worldwide; the largest numbers of injectors were found in China, the USA, and Russia, where mid-estimates of HIV prevalence among injectors were 12%, 16%, and 37%, respectively. HIV prevalence among injecting drug users was 20–40% in five countries and over 40% in nine. We estimate that, worldwide, about 3·0 million (range 0·8–6·6 million) people who inject drugs might be HIV positive. Interpretation The number of countries in which the injection of drugs has been reported has increased over the last decade. The high prevalence of HIV among many populations of injecting drug users represents a substantial global health challenge. However, existing data are far from adequate, in both quality and quantity, particularly in view of the increasing importance of injecting drug use as a mode of HIV transmission in many regions. Funding UN Office on Drugs and Crime; Australian National Drug and Alcohol Research Centre, University of New South Wales.

This paper reviews the performance of the syringe exchange programmes (SEPs) in Manipur, northeast India, with the objective of identifying good practice, and areas that require improvement. The paper also examines contextual and structural factors in Manipur that inhibit optimal functioning of SEPs and hinder behaviour change, and argues that these factors need to be addressed as part of any endeavour aimed at improving services and programme coverage in the future.

Since the introduction of methadone in the 1960s, a variety of other substances have been proposed and piloted as substitutes for opioids. Recently, with the growing problem of HIV/AIDS and other blood-borne infections among drug users, oral substitution therapy has been given more importance. This paper reports on findings of an exploratory study examining the possibility of using liquid extract of poppy straw (broken pieces of poppy shell after extraction of opium seeds) as a substitute for heroin. The paper is based on observations of drug users in Calcutta, India, found drinking liquid extract of poppy straw, interviews with a sample of 103 injecting drug users (IDUs) and 39 non-IDUs, and chemical analysis of poppy straw extract. Eighty-two percent of IDUs and 72% of non-IDUs who had used poppy straw in the last year reported that it provided at least some relief from withdrawal from heroin. Findings from these two sub-studies suggest the possibility of using liquid extract of poppy straw as a substitution for heroin as well as a novel harm reduction approach for reducing blood-borne infections.

HIV and drug use continue to pose challenges in tandem*/like a bicycle with seats for two, one riding behind the other*/to the practitioners of public health as well as intervention researchers worldwide. For example, while cities in Australia have recorded a low HIV prevalence in injection drug users (IDUs) (Wodak and Lurie, 1997) and New York has reported declines in HIV incidence among IDUs (Des Jarlais et al., 2000), Kathmandu*/the capital city of Nepal*/has experienced initial containment followed by explosive spread of HIV among IDUs in the last 6 years (Pokharel et al., 2000). These challenges are made tougher by a few hurdles, such as the assumption that the HIV epidemic in heterosexuals is independent from that in IDUs and the intermittent switch from non-injection forms of drug use to injecting under various socio-political influences. Many national HIV/AIDS Control Programmes in developing countries also add to these challenges by having most of their resources spent on breaking the chain of transmission in the population groups who are vulnerable to getting HIV through sex and by having abysmally low support for interventions targeting injection drug users. The mainstay of this approach is formed by the belief that HIV epidemics in IDUs do not contribute significantly to the overall HIV epidemic. Evidence, however, suggests the contrary. Lowndes et al. (2003) identify an interplay of forces which contribute towards conditions favourable for the heterosexual spread of HIV in the Russian Federation, which since 1996 has witnessed a series of large and explosive HIV epidemics among IDUs in different cities. Such a rapid spread of HIV among IDUs reminds us of the HIV epidemic among IDUs in Manipur, a northeastern state of India sharing a border with Myanmar. This response looks back to the past when the epidemic happened in Manipur, as well as taking account of current research evidence to examine critically whether one really needs to bother about HIV epidemics in injectors. Twelve years ago, in the winter of 1989, an outbreak of HIV occurred among a large number of injection heroin users of Manipur (Sarkar et al., 1991). The virus not only infected more than 50% of the local IDUs within 9 months, but it spread into other population groups as well. Some 45% of the non-injecting wives of IDUs (Panda et al., 2000) and 1.2% of the antenatal clinic-attending women (representing female general population) in the state (NACO 1997 /1998) contracted the virus within the next 5 years. A small study from Manipur, conducted in 1997, recruited female sex workers operating from the streets of Imphal, the capital city (there is no brothel-based sex industry in Manipur) and revealed that while 20% of those who had never injected drugs were HIV positive, 57% of female injection drug users involved in sex work had HIV (Panda et al., 2001). About one-third of the female IDUs involved in sex work in this study had male IDUs as their regular sex partners. Lowndes et al. (2003) document a similar progression of HIV among different population groups in the Russian Federation, highlighting different links between IDU and non-IDU populations that may be responsible for generating a wider spread of HIV in countries where epidemic outbreaks first emerged among IDUs. While it took some time for policymakers to see how different pieces of information relating to the progression of HIV in Manipur were parts in one jigsaw puzzle, an early attempt to do so in Russia and elsewhere would certainly pay dividends for HIV prevention. Otherwise, a familiar story of the diffusion of injection drug use in a new area followed by rapid HIV spread among IDUs and subsequent spread to non-IDU population groups may repeat itself. The evidence generated through the randomised controlled trials in African countries on the role of improved STD management in reducing HIV incidence in the early phase of HIV epidemics (Grosskurth et al., 2000) emphasises how STIs could play a * Tel.: /91-332-5910-334; fax: /91-332-3376-290. E-mail address: samiran_panda@rediffmail.com (S. Panda). International Journal of Drug Policy 14 (2003) 83 /85

Sir—Of the 126 countries worldwide with injecting-drug users, 98 report HIV-1 among the population of injecting-drug users. Since the publication of C Y Ou and colleagues’ 1993 report, a general assumption is that HIV-1 epidemic among injectingdrug users was caused by infection with subtype B. Their finding of a preponderance of subtype B among the injectors and subtype E among the female sex workers led many health professionals to believe that the epidemics of HIV-1 among injectingdrug users and heterosexuals were independent. The finding that subtype B HIV-1 did not readily infect Langhans cells supported the hypothesis that the epidemic in injecting-drug users was not likely to spread easily to the heterosexual population. There are two concerns about this assumption; first, heterosexual transmission of subtype B does occur; and second, most injecting-drug users in Thailand, Vietnam, China, and Manipur (India) are no longer infected with subtype B. The only subtype reported in injecting-drug users in Vietnam is subtype E, and an increasingly high proportion of injecting drug users in Thailand are now infected with subtype E rather than subtype B. In Manipur, we found that most injecting-drug users were infected with subtype C, and reports suggest that this subtype C is also common among injectors in Yunnan. Both subtypes C and E are readily transmitted by heterosexual contact, so an epidemic in injecting-drug users does pose a threat to the mainstream population, most of whom are heterosexual. Intensive intervention strategies to stop the HIV-1 epidemic should start as soon as HIV-1 infection is first identified among injecting-drug users in a country.