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.

Safety and clinical efficacy of human rabies immunoglobulin in post exposure prophylaxis for category III animal exposures.

The human rabies immunoglobulin (HRIG) is a life-saving immune biological essential for all category III animal exposures. It provides neutralizing antibodies at the site of exposure until the body can produce vaccine-mediated antibodies. We conducted this study to determine the safety and clinical efficacy of an HRIG being used presently for post-exposure prophylaxis (PEP) and to strengthen the existing evidence for its further usage. We conducted a prospective cohort study in 123 subjects with category III animal exposures at the KIMS Hospital and Research Center, Bangalore, India. Post-exposure prophylaxis (PEP) with wound toilet, a single application of HRIG, and a full course of anti-rabies vaccination were provided to all the study subjects. The volume of HRIG was calculated according to the body weight, and all the wounds were infiltrated as was anatomically feasible. All the study subjects were followed up for immediate and delayed adverse events (AE), both local and systemic. Subsequently, all the subjects were followed up for 6 months to demonstrate the clinical efficacy of PEP. The incidence of AEs was 11.4% including local pain, erythema, itching, headache, body ache, fever, and malaise. All AEs were mild and subsided without any complications. All the study subjects were healthy and alive after 6 months following the administration of HRIG, along with a full course of anti-rabies vaccine. Our study provides evidence of safety and clinical efficacy of HRIG for category III animal exposures and supports its continued usage.

Defining the volume of rabies immunoglobulins/ rabies monoclonal antibodies requirement for wound infiltration of category III animal exposures - an exploratory study.

WHO recommends infiltration of rabies immunoglobulins/rabies monoclonal antibodies as anatomically possible, into or close to all category III animal bite wound(s)/exposures for post exposure prophylaxis. The volume required for wound infiltration depending upon the site/size/severity of wound is yet to be defined for guiding the treating physicians. This study aimed to determine the volume of rabies immunoglobulin/rabies monoclonal antibody required for wound infiltration depending upon the site, size, and severity. A prospective cohort study was conducted including category III animal exposures at the anti-rabies clinic, KIMS hospital and Research Center, Bangalore, India. The volume of rabies immunoglobulins/rabies monoclonal antibodies required for wound infiltration, depending on site, severity, and size was determined. All the subjects were followed for 6 months to demonstrate the safety and clinical efficacy of post exposure prophylaxis. The present study included 717 subjects having 1428 bite wounds. There was a significant difference in the median volume required for wound infiltration based on site, size, and severity of bite wounds. However, on pairwise comparison; the median volume among all the pairs for only wound size was found to be statistically significant. Supportively, a strong positive correlation was seen with the size of wound and volume infiltrated. The volume of rabies immunoglobulin/rabies monoclonal antibodies required for wound infiltration shall be determined according to size of wounds, i.e. 1 ml for <1 cm wound, 3 ml for 1-5 cm wound, and 5 ml for >5 cm wound.

Boosting effect of purified chick embryo cell rabies vaccine using the intradermal route in persons previously immunized by the intramuscular route or vice versa.

BACKGROUND: At present, in the event of re-exposure to rabies, 2 booster doses are recommended for people who have been previously vaccinated with cell culture rabies vaccines by the conventional intramuscular route. As the intradermal route of vaccination is likely to be introduced in the future, we investigated the immune response to a cell culture rabies vaccine after crossing over from the intramuscular to the intradermal route and vice versa. METHODS: Twenty healthy adult volunteers who had received a primary course of rabies vaccination with purified chick embryo cell rabies vaccine by either the intramuscular (n = 10) or intradermal (n = 10) route received booster vaccination with the same vaccine by the alternative route. The regimen used was 0.1 ml of vaccine by the intradermal route at two sites (deltoid area) for the intramuscular group, or 1 ml of vaccine by the intramuscular route (deltoid muscle) to the intradermal group on days 0 and 3. RESULTS: There was a 15-fold rise in the rabies virus neutralizing antibody response both by the intradermal and intramuscular routes of booster vaccination (p < 0.0001). Thus, the change of route of purified chick embryo cell booster vaccination did not alter the anamnestic immune response to the vaccine. No side-effects were observed after vaccination with either of the routes. CONCLUSION: Purified chick embryo cell vaccine was found to be safe and immunologically efficacious following booster vaccination after cross-over from the intradermal to the intramuscular route and vice versa.

Assessing the safety of post-exposure rabies immunization in pregnancy.

Fourteen pregnant women who received rabies post-exposure prophylaxis (PEP) at the anti-rabies clinic (ARC) of Kempegowda Institute of Medical Sciences (KIMS) were followed up for assessing the safety of modern rabies vaccines and equine rabies immunoglobulin (ERIG) in pregnancy. The women were in the age range of 18-28 years, mostly from urban area (64%) and exposed to suspect rabid dogs (86%). They had received purified vero cell rabies vaccine (Verorab = 8 and Abhayrab = 4), purified chick embryo cell vaccine (Rabipur = 2) by Essen regimen; and equine rabies immunoglobulin (Equirab = 7 and Pasteur anti-rabies serum = 1). None of the pregnant women reported any adverse events to either vaccine or equine rabies immunoglobulin. All had safe vaginal deliveries and in all cases both the mother and the child were found to be healthy and normal.

Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines. Results of a meta-analysis.

A meta-analysis was done to study the relationship between antigenecity and immunogenecity of human rabies vaccines. The data of ten cell culture human rabies vaccine studies conducted at a single centre during 1993-2004 were used in the study. The vaccines studied included Purified Chick Embryo Cell Vaccine (Kaketsuken, Japan and Rabipur, India), Purified Vero cell Rabies Vaccine (Verorab, France), Human Diploid Cell Vaccine (MIRV, France and Rabivax, Adsorbed and Lyophilized, India) and Rhesus Diploid Rabies Vaccine (adsorbed, USA). Interestingly, it was revealed that an higher antigenecity of rabies vaccines viz. potency of > or = 5 IU per single intramuscular dose did not result in significantly higher immunogenecity, as measured by rabies virus neutralizing antibody (RVNA) titers in the vaccinees, both on day 14 (t = 0.42, p > 0.66, GMR = 1.06, 95% CI of GMR = 0.82, 1.37) and day 90 (t = 0.80, p > 0.43, GMR = 1.15, 95% CI of GMR = 0.74, 1.14). However, as there are no reports of meta-analysis of cell culture human rabies vaccine trials, to confirm this observation the authors recommend further studies in this regard.