Seropersistence of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine): 6-month follow-up of a randomized, controlled, observer-blind, phase 2/3 immuno-bridging study in Indian adults.

AZD1222 (ChAdOx1 nCoV-19) is a replication-deficient adenoviral vectored coronavirus disease-19 (COVID-19) vaccine that is manufactured as SII-ChAdOx1 nCoV-19 by the Serum Institute of India Pvt Ltd following technology transfer from Oxford University/AstraZeneca. The non-inferiority of SII-ChAdOx1 nCoV-19 with AZD1222 was previously demonstrated in an observer-blind, phase 2/3 immuno-bridging study (trial registration: CTRI/2020/08/027170). In this analysis of immunogenicity and safety data 6 months post first vaccination (Day 180), 1,601 participants were randomized 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (immunogenicity/reactogenicity cohort n = 401) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort n = 1,200). Immunogenicity was measured by anti-severe acute respiratory syndrome coronavirus 2 spike (anti-S) binding immunoglobulin G and neutralizing antibody (nAb) titers. A decline in anti-S titers was observed in both vaccine groups, albeit with a greater decline in SII-ChAdOx1 nCoV-19 vaccinees (geometric mean titer [GMT] ratio [95% confidence interval (CI) of SII-ChAdOx1 nCoV-19 to AZD1222]: 0.60 [0.41-0.87]). Consistent similar decreases in nAb titers were observed between vaccine groups (GMT ratio [95% CI]: 0.88 [0.44-1.73]). No cases of severe COVID-19 were reported following vaccination, while one case was observed in the placebo group. No causally related serious adverse events were reported through 180 days. No thromboembolic or autoimmune adverse events of special interest were reported. Collectively, these data illustrate that SII-ChAdOx1 nCoV-19 maintained a high level of immunogenicity 6 months post-vaccination. SII-ChAdOx1 nCoV-19 was safe and well tolerated.

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.

Post-marketing safety surveillance of the rotavirus vaccine in India.

Background: ROTASIIL, an oral live attenuated bovine-human reassortant pentavalent rotavirus vaccine, was approved in 2017. This post-marketing surveillance (PMS) was conducted to collect real-world data on the safety of ROTASIIL in India. Methods: Observational, active PMS was conducted in approximately 10,000 infants aged ≥ 6 weeks. ROTASIIL was administered as a 3-dose regimen, at least 4 weeks apart, beginning at ≥ 6 weeks of age concomitantly with other Expanded Programme on Immunization (EPI) vaccines. Participants were followed for one month after the last dose. The adverse events (AEs) and serious adverse events (SAEs), including intussusception (IS) reported during the follow up period were collected. Findings: A total of 9940 infants were enrolled and were considered for safety analysis. Around 9913 (99.7 %) infants received 2 doses, while 9893 (99.5 %) infants completed all three doses. Total 3693 AEs were reported in 2516 (25.3 %) participants. Most of these AEs were pyrexia (78.01 % of events) and injection-site reactions (19.14 % of events). Nearly all AEs were causally unrelated to orally administered ROTASIIL and could be caused by the concomitant injectable vaccines. Only 4 AEs (2 events of vomiting and 1 event each of discomfort and pyrexia) in 4 (<0.1 %) participants could be related to ROTASIIL. AEs were of mild or moderate severity and all resolved without any sequelae. A total of 2 SAEs (acute otitis media and skull fracture) were reported in 2 (<0.1 %) participants and were not related to ROTASIIL and recovered without sequelae. No case of IS was reported. Interpretation: ROTASIIL was safe and well tolerated in this study. No safety concerns were reported. Funding: The study was funded by SIIPL which is the manufacturer of the study product.

Safety and Immunogenicity of SARS-CoV-2 Recombinant Spike Protein Vaccine in Children and Adolescents in India: A Phase 2-3 Randomized Clinical Trial.

Importance: The recombinant COVID-19 vaccine NVX-CoV2373 has demonstrated efficacy of approximately 90% in adults; however, its safety and efficacy in children is unknown. Objective: To assess the noninferiority of SII-NVX-CoV2373 in children and adolescents compared to adults and to evaluate its safety in comparison with placebo. Design, Setting, and Participants: This phase 2-3 observer-blind randomized clinical trial was conducted in 2 cohorts, children (aged 2 to 11 years) and adolescents (aged 12 to 17 years) between August 2021 and August 2022. Participants were randomized 3:1 to SII-NVX-CoV2373 or placebo and monitored for 179 days. The participants, study team, and laboratory staff were blinded. This was a multicenter study conducted across 10 tertiary care hospitals in India. Exclusion criteria included previous COVID-19 infection or vaccination, immunocompromised condition, and immunosuppressive medications. Interventions: Two doses of 0.5-mL SII-NVX-CoV2373 or placebo were administered intramuscularly on days 1 and 22. Main Outcomes and Measures: Primary outcomes were geometric mean titer ratio of both anti-spike (anti-S) IgG and neutralizing antibodies (NAbs) between both pediatric age groups to that of adults on day 36. Noninferiority was concluded if the lower bound of 95% CI of this ratio was greater than 0.67 for each age group. Both the antibodies were assessed for the index strain and for selected variants at various time points. Solicited adverse events (AEs) were recorded for 7 days after each vaccination, unsolicited AEs were recorded for 35 days, and serious AEs and AEs of special interest were recorded for 179 days. Results: A total of 460 children in each age cohort were randomized to receive vaccine or placebo. The mean (SD) age was 6.7 (2.7) years in the child cohort and 14.3 (1.6) years in the adolescent cohort; 231 participants (50.2%) in the child cohort and 218 in the adolescent cohort (47.4%) were female. Both anti-S IgG and NAb titers were markedly higher in the SII-NVX-CoV2373 group than in the placebo group on both day 36 and day 180. The geometric mean titer ratios compared to those in adults were 1.20 (95% CI, 1.08-1.34) and 1.52 (95% CI, 1.38-1.67) for anti-S IgG in adolescents and children, respectively; while for NAbs, they were 1.33 (95% CI, 1.17-1.50) and 1.93 (95% CI, 1.70-2.18) in adolescents and children, respectively, indicating noninferiority. SII-NVX-CoV2373 also showed immune responses against variants studied. Injection site reactions, fever, headache, malaise, and fatigue were common solicited AEs. There were no AEs of special interest and no causally related serious AEs. Conclusions and Relevance: SII-NVX-CoV2373 was safe and well tolerated in children and adolescents in this study. The vaccine was highly immunogenic and may be used in pediatric vaccination against COVID-19. Trial Registration: Clinical Trials Registry of India Identifier: CTRI/2021/02/031554.

Active safety surveillance of rabies monoclonal antibody and rabies vaccine in patients with category III potential rabies exposure.

Background: A vero cell-based inactivated Rabies Vaccine (Rabivax-S) and Rabies Human Monoclonal Antibody (Rabishield) have been approved since 2016. A post-marketing surveillance was conducted in India from 2020 to 2021 to gather real world safety data on Rabivax-S and Rabishield. Methods: This was non-interventional active surveillance in patients with category III potential rabies exposure who were administered a post-exposure prophylaxis (PEP) regimen (Rabishield and Rabivax-S) by their healthcare providers (HCPs) as per the dosages and regimens mentioned in the package insert approved by the Indian regulators. The approved schedule for PEP was local infiltration of Rabishield on Day 0 and five doses of Rabivax-S on Day 0, 3, 7, 14, and 28 (Intramuscular route, IM) or four doses of Rabivax-S on Day 0, 3, 7, and 28 (Intradermal route, ID). The primary objective of this surveillance was to generate real-world evidence on the safety and tolerability of Rabishield and Rabivax-S. All patients enrolled in the surveillance were required to report any adverse events (AEs) occurring up to Day 31 after initiation of PEP (administration of Rabishield and the first dose of Rabivax-S) to their HCP. Findings: A total of 1000 patients with category III potential rabies exposure were enrolled across India. 991 patients received the PEP regimen with IM Rabivax-S while 9 received a PEP regimen with the ID regimen. While 32% of the patients were <12 years of age, 11.8% were ≥12 to <18 years of age and 56.2% were ≥18 years of age. The entire PEP regimen was completed by 97.3% of the enrolled patients. A total of 69 AEs were reported in 64 patients. Out of these, 49 AEs in 47 patients were assessed as causally related to the study products (26 with Rabishield and 23 with Rabivax-S). The majority of the AEs were mild and all recovered without any sequelae. One serious adverse event (SAE) of fracture of the hand was reported which was not related to either Rabishield or Rabivax-S. No case of rabies was reported. Interpretation: Rabishield and Rabivax-S have an excellent safety profile and are well tolerated. No participant developed rabies during 31 day follow up. Funding: The PMS was funded by Serum institute of India Private Limited which is the manufacturer of the study products.

Safety and immunogenicity of SII-NVX-CoV2373 (COVID-19 vaccine) in adults in a phase 2/3, observer-blind, randomised, controlled study.

Background: NVX-CoV2373, a Covid-19 vaccine was developed in the USA with ∼90% efficacy. The same vaccine is manufactured in India after technology transfer (called as SII-NVX-CoV2373), was evaluated in this phase 2/3 immuno-bridging study. Methods: This was an observer-blind, randomised, phase 2/3 study in 1600 adults. In phase 2, 200 participants were randomized 3:1 to SII-NVX-CoV2373 or placebo. In phase 3, 1400 participants were randomized 3:1 to SII-NVX-CoV2373 or NVX-CoV2373 (940 safety cohort and 460 immunogenicity cohort). Two doses of study products (SII-NVX-CoV2373, NVX-CoV2373 or placebo) were given 3 weeks apart. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 to NVX-CoV2373 in terms of geometric mean ELISA units (GMEU) ratio of anti-S IgG antibodies 14 days after the second dose (day 36) and to determine the incidence of causally related serious adverse events (SAEs) through 180 days after the first dose. Anti-S IgG response was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) and neutralizing antibodies (nAb) were assessed by a microneutralization assay using wild type SARS CoV-2 in participants from the immunogenicity cohort at baseline, day 22, day 36 and day 180. Cell mediated immune (CMI) response was assessed in a subset of 28 participants from immunogenicity cohort by ELISpot assay at baseline, day 36 and day 180. The total follow-up was for 6 months. Trial registration: CTRI/2021/02/031554. Findings: Total 1596 participants (200 in Phase 2 and 1396 in Phase 3) received the first dose. SII-NVX-CoV2373 was found non-inferior to NVX-CoV2373 (anti-S IgG antibodies GMEU ratio 0.91; 95% CI: 0.79, 1.06). At day 36, there was more than 58-fold rise in anti-S IgG and nAb titers compared to baseline in both the groups. On day 180 visit, these antibody titers declined to levels slightly lower than those after the first dose (13-22 fold-rise above baseline). Incidence of unsolicited and solicited AEs was similar between the SII-NVX-CoV2373 and NVX-CoV2373 groups. No adverse event of special interest (AESI) was reported. No causally related SAE was reported. Interpretation: SII-NVX-CoV2373 induced a non-inferior immune response compared to NVX-CoV2373 and has acceptable safety profile. Funding: SIIPL, Indian Council of Medical Research, Novavax.

A phase 2/3, participant-blind, observer-blind, randomised, controlled study to assess the safety and immunogenicity of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine) in adults in India.

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.

Safety and tolerability of a liquid bovine rotavirus pentavalent vaccine (LBRV-PV) in adults.

BACKGROUND: Rotavirus Gastroenteritis (RVGE) is an important global public health problem. Recently a Lyophilized Pentavalent Human Bovine Reassortant Rotavirus vaccine (BRV-PV, Rotasiil) was licensed in India. A Liquid formulation of the same vaccine (LBRV-PV) was tested in a Phase I clinical trial. METHODS: Total 20 healthy adults were given a single oral dose of LBRV-PV and were followed for one month for safety outcomes: immediate reactions, solicited reactions, unsolicited adverse events and serious adverse events. RESULTS: All 20 adults completed the study without any major protocol deviations. No immediate reaction, solicited reactions and unsolicited adverse events were reported during the study. No clinically significant changes were seen in the vital parameters and safety laboratory test results. CONCLUSIONS: LBRV-PV developed in India was safe and well tolerated in adults. Further clinical development of this vaccine in infants should be undertaken. Trial Registration - CTRI/2015/11/006,384.

Prescribing practices of topical corticosteroids in the outpatient dermatology department of a rural tertiary care teaching hospital.

BACKGROUND: Inappropriate or excessive use of topical corticosteroids can lead to cutaneous and systemic adverse effects which occur more commonly with the use of very potent steroids. Monitoring and analysis of the prescription practices of topical steroids can help to achieve rational prescription of these drugs. AIM: The present study was carried out to study and analyze the pattern of prescribing topical corticosteroids among outpatients attending the dermatology clinic in a rural tertiary care and teaching hospital, Ambajogai, Maharashtra. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted for a duration of two months from August 2011 to September 2011, and 500 prescriptions were randomly collected from the dermatology pharmacy and analyzed. RESULTS: About 66% of the prescriptions contained four to five drugs per prescription. Topical steroids were given in 28.4% of all the prescriptions. In almost all the prescriptions, strength, quantity of the steroid to be used, frequency, site, and duration of application was not mentioned. The chief complaints and diagnoses were not mentioned in about 85% of the prescriptions for topical corticosteroids. About 94.36% of the prescriptions contained very potent steroids. CONCLUSION: Inadequate prescribing information is a clear characteristic of the dermatological prescriptions containing topical corticosteroids. Doctors should be educated about the importance of giving patients sufficient information regarding the use of steroids. There is a need to revise hospital formulary where low-potency steroids can also be included along with potent ones so that the latter can be avoided in conditions where they are unnecessary.

Adverse drug reaction profile of anti-snake venom in a rural tertiary care teaching hospital.

OBJECTIVES: The study was carried out with the aim of evaluation of the adverse drug reaction profile of anti-snake venom serum (ASV) in a rural tertiary care hospital. METHODS: An observational study was conducted in SRTR Medical College, Ambajogai, Maharashtra, India. A total number of 296 indoor case papers of snake bite from February to September 2011 and June to August 2012 were retrieved from the record section and the antivenom reactions were assessed. In addition, basic epidemiological data and prescribing practices of ASV were also analyzed. RESULTS: Vasculotoxic snake bites were more common (50.61%) than neuroparalytic ones (22.56%). Mild envenomation was the commonest presentation. A total of 92 (56.10%) patients who received ASV suffered from antivenom reactions. The most common nature of reaction was chills, rigors (69.56%) followed by nausea and vomiting (34.8%). 10-15% patients suffered from moderate to severe reactions like hypotension and sudden respiratory arrest. We did not find any dose response relationship of ASV to risk of reactions (odds ratio 0.37). Intradermal sensitivity test was performed in about 72% cases. CONCLUSION: Our study showed a higher incidence of reactions to ASV at our institute.