Corrigendum to "Second round statewide sentinel-based population survey for estimation of the burden of active infection and anti-SARS-CoV-2 IgG antibodies in the general population of Karnataka, India, during January-February 2021" [IJID Regions Vol 1(2021) pages 107-116].

[This corrects the article DOI: 10.1016/j.ijregi.2021.10.008.].

The burden of active infection and anti-SARS-CoV-2 IgG antibodies in the general population: Results from a statewide sentinel-based population survey in Karnataka, India.

OBJECTIVE: To estimate the burden of active infection and anti-SARS-CoV-2 IgG antibodies in Karnataka, India, and to assess variation across geographical regions and risk groups. METHODS: A cross-sectional survey of 16,416 people covering three risk groups was conducted between 3-16 September 2020 using the state of Karnataka's infrastructure of 290 healthcare facilities across all 30 districts. Participants were further classified into risk subgroups and sampled using stratified sampling. All participants were subjected to simultaneous detection of SARS-CoV-2 IgG using a commercial ELISA kit, SARS-CoV-2 antigen using a rapid antigen detection test (RAT) and reverse transcription-polymerase chain reaction (RT-PCR) for RNA detection. Maximum-likelihood estimation was used for joint estimation of the adjusted IgG, active and total prevalence (either IgG or active or both), while multinomial regression identified predictors. RESULTS: The overall adjusted total prevalence of COVID-19 in Karnataka was 27.7% (95% CI 26.1-29.3), IgG 16.8% (15.5-18.1) and active infection fraction 12.6% (11.5-13.8). The case-to-infection ratio was 1:40 and the infection fatality rate was 0.05%. Influenza-like symptoms or contact with a COVID-19-positive patient were good predictors of active infection. RAT kits had higher sensitivity (68%) in symptomatic people compared with 47% in asymptomatic people. CONCLUSION: This sentinel-based population survey was the first comprehensive survey in India to provide accurate estimates of the COVID-19 burden. The findings provide a reasonable approximation of the population immunity threshold levels. Using existing surveillance platforms coupled with a syndromic approach and sampling framework enabled this model to be replicable.

Second round statewide sentinel-based population survey for estimation of the burden of active infection and anti-SARS-CoV-2 IgG antibodies in the general population of Karnataka, India, during January-February 2021.

Objective: Demonstrate the feasibility of using the existing sentinel surveillance infrastructure to conduct the second round of the serial cross-sectional sentinel-based population survey. Assess active infection, seroprevalence, and their evolution in the general population across Karnataka. Identify local variations for locally appropriate actions. Additionally, assess the clinical sensitivity of the testing kit used on account of variability of antibody levels in the population. Methods: The cross-sectional study of 41,228 participants across 290 healthcare facilities in all 30 districts of Karnataka was done among three groups of participants (low, moderate, and high-risk). The geographical spread was sufficient to capture local variations. Consenting participants were subjected to real-time reverse transcription-polymerase chain reaction (RT-PCR) testing, and antibody (IgG) testing. Clinical sensitivity was assessed by conducting a longitudinal study among participants identified as COVID-19 positive in the first survey round. Results: Overall weighted adjusted seroprevalence of IgG was 15.6% (95% CI: 14.9-16.3), crude IgG prevalence was 15.0% and crude active infection was 0.5%. Statewide infection fatality rate (IFR) was estimated as 0.11%, and COVID-19 burden estimated between 26.1 to 37.7% (at 90% confidence). Further, Cases-to-infections ratio (CIR) varied 3-35 across units and IFR varied 0.04-0.50% across units. Clinical sensitivity of the IgG ELISA test kit was estimated as ≥38.9%. Conclusion: We demonstrated the feasibility and simplicity of sentinel-based population survey in measuring variations in subnational and local data, useful for locally appropriate actions in different locations. The sentinel-based population survey thus helped identify districts that needed better testing, reporting, and clinical management. The state was far from attaining natural immunity during the survey and hence must step up vaccination coverage and enforce public health measures to prevent the spread of COVD-19.

Appraisal of surveillance of human rabies and animal bites in seven states of India.

BACKGROUND: The key to understanding the burden of animal bites and rabies lies in accurate and timely data with the help of proper surveillance system across the country. Such a surveillance system needs to be evaluated also for a programmatic purpose. OBJECTIVES: The present study was conducted to appraise the surveillance system of human rabies and animal bites in seven states of India and also to describe the characteristics of human rabies cases in the states. METHODS: The record-based study was conducted from July to December 2017. The survey team collected information about the surveillance status of human rabies from the infectious diseases hospitals and animal bites from integrated disease surveillance programme (IDSP) offices of the respective states for 2012-2016. At the national level, also number of animal exposures and the human rabies cases were collected from the Central Bureau of Health Intelligence and IDSP and compared for concordance. RESULTS: There was a gross underreporting of human rabies from the states to Government of India, and there was no concordance in the reports of animal bites between the IDSP offices of the states and NCDC, New Delhi, India. There was a gradual decline in the reported cases of human rabies from the states during the 5-year period of 2012-2016, attributable to improvement in the overall rabies postexposure prophylaxis services. The documentation of information of the human rabies cases was poor in the infectious disease hospitals. CONCLUSION: The surveillance system on human rabies and animal bites in India has to be improved under the national rabies control program to eliminate rabies by the year 2030.

Facilities and services of postexposure prophylaxis in anti-rabies clinics: A national assessment in India.

BACKGROUND: The rabies postexposure prophylaxis (PEP) is provided through anti-rabies clinics in the country. It was considered important to assess their facilities under a nationwide multi-centric survey. OBJECTIVES: The objective of this study is to assess the facilities available for PEP at the anti-rabies clinics and to ascertain the PEP provided at the anti-rabies clinics. METHODS: The cross-sectional assessment was made from May 2017 to January 2018 in selected seven states of India. Thirty-five anti-rabies clinics from both Government and private; urban and rural areas from the states were assessed by an expert team using a pretested checklist for facilities and services available for PEP. RESULTS: On an average, 10 new animal bite cases were attended at each anti-rabies clinic per day. The cold chain facilities for rabies biologicals were satisfactory. The facilities for wound washing (54.3%) and the use of antiseptics to animal bite wounds were not adequate. Rabies vaccines were administered by intramuscular in 54.3% and by intradermal route in 45.7% of the cases. The vaccine stock-outs were reported only in the government sector (18.5%). The type of rabies immunoglobulin (RIG) used was equine (63.2%) and human (36.8%); given free of cost in 40% of Anti rabies clinics. The local wound infiltration of RIG was in practice at 58.6% of anti-rabies clinics. The stock-out of RIG was more in private (50%) hospitals than in Government (40.7%) hospitals. CONCLUSION: The facilities available for PEP at the anti-rabies clinics were inadequate and have to be improved across the country.

Market mapping and landscape analysis of human rabies biologicals in India.

BACKGROUND: Rabies vaccines and immunoglobulins are lifesaving in humans following animal exposures. These biologicals should continuously be available throughout the year to prevent and eliminate human rabies by 2030. OBJECTIVES: The present study aimed at assessing availability of different kinds of human rabies biologicals in the country and undertaking market mapping and landscape analysis of human rabies biologicals in India. METHODS: The study comprising both quantitative and qualitative approach was conducted from May to November 2017 as a part of the Indian multicentric rabies survey by Association for Prevention and Control of Rabies in India. All stakeholders (agencies/personnel) associated with rabies biologicals were the study units/participants. Required data were generated through brainstorming sessions with key stakeholders; reviewing of databases/existing literature; conducting in-depth surveys; interviewing; focused group discussions, etc. RESULTS: Two types of cell culture rabies vaccines are available in the country manufactured by different pharmaceutical companies; most of the vaccines are indigenously produced and the market size of the rabies vaccines is about INR 125 crores with highest sales in the northern region followed by South. Likewise, there are 2 types of immunoglobulin available, i.e., equine rabies immunoglobulins (RIGs), which are indigenously produced and human RIGs, which are imported. The market value of RIGs is about INR 83 crores. A novel rabies monoclonal antibody is also been marketed in the country from November 2017. CONCLUSIONS: There are many lacunas in the market availability of rabies biologicals in different parts of the country; therefore, a significant expansion/shift in focus must be considered, through rigorous strategic planning process.

Background paper for developing a policy for the use of rabies biologicals and vaccination of humans in India.

National Rabies Control Programme, India, is in operation since 2012-2013 without much impact due to poor funding and no set policy for the rabies prevention and control. An effort was made to develop a draft policy paper which can help the Government of India to develop a national rabies vaccination policy for humans and for achieving the goal of zero dog-mediated human rabies deaths by the year 2030. A technical stakeholders meeting was held under the chairmanship of the Drug Controller General of India at New Delhi in December 2017 to discuss the problems and solutions for providing essential rabies postexposure prophylaxis (PEP). The following problems and dilemmas were identified: frequent shortages of life-saving rabies vaccines and rabies immunoglobulin for PEP; as rabies vaccines are mostly procured by the state governments that often face resource crunch and hurdles in logistics within the states; production levels of rabies biologicals in the public sector are low; and the export of rabies biologicals from the private sector needs to be critically evaluated in the context of frequent stock-outs in the domestic market and also the national vaccine security.

Safety and immunogenicity study of a new purified chick embryo cell rabies vaccine Vaxirab-N (Pitman-Moore strain) manufactured in India.

Zydus Cadila Health care, India developed a new purified chick embryo cell rabies vaccine (PCECV, Vaxirab-N; 1 mL) by adapting Pitman-Moore strain of virus on to the chick embryo fibroblast cell line in 2006. During 2007-10, a series of safety and immunogenicity studies were conducted as per ICH-GCP guidelines after obtaining permission from Drug Controller General of India. In the first study, Vaxirab-N was administered to 35 healthy adult volunteers by intramuscular (IM) route using pre exposure regimen. The geometric mean concentration (GMC) of rabies virus neutralizing antibody (RvnAb) of 7.5 IU/mL on day 35. In the second study, Vaxirab-N was administered to 35 healthy adult volunteers using simulated post- exposure prophylaxis regimen by IM route. A GMC of 6.3 IU/mL on day 14, 13.2 IU/mL on day 28 and 8.6 IU/mL on day 90 was obtained. In the third study, Vaxirab-N administered by intradermal (ID) route using Updated Thai Red Cross (TRC) regimen in 36 healthy adult volunteers showed GMC of 7.8 IU/mL on day 14, 11.5 IU/mL on day 28 and 6.0 IU/mL on day 90. The 4th study was multi centric and Vaxirab-N was administered to 129 animal bite cases by IM route using post-exposure Essen regimen. The GMC following this schedule was 8.2 IU/mL on day 14, 13.01 IU/mL on day 28, 7.92 IU/mL on day 90 and 3.72 IU/mL on day 180. Mild to moderate adverse events were reported to Vaxirab-N but no serious adverse events were reported in any of these studies. In conclusion, Vaxirab-N developed by Zydus Cadila was found to be safe and immunogenic by both intramuscular and intradermal route and is recommended for rabies prophylaxis (CTRI No. 2010/091/000055 and 2010/091/000509).

Evaluation of a one week intradermal regimen for rabies post-exposure prophylaxis: results of a randomized, open label, active-controlled trial in healthy adult volunteers in India.

The currently recommended intradermal regimen for post-exposure prophylaxis spreads over a month period which many times lead to low compliance from the patients. There is a need to introduce and evaluate short course regimens to overcome this problem. This study was conducted to evaluate the immunogenicity and safety of a "new one week intradermal regimen" for rabies post-exposure prophylaxis. A total of 80 healthy adult volunteers were enrolled and allocated randomly either to purified chick embryo cell (PCECV) rabies vaccine or purified verocell rabies vaccine (PVRV), 40 in each group. Each subject received intradermally one of the vaccines , using the one week regimen (4-4-4). Blood samples were collected on Days 0, 7, 14, 28,180 and 365 for estimation of rabies virus neutralizing antibody (RVNA) concentration. The sera samples were analyzed by rapid fluorescent focus inhibition test (RFFIT). All subjects in both the groups had adequate RVNA concentration of  0.5 IU/mL from day 14 to till day 180 and the difference of geometric mean concentrations between the two groups was not significant (P > 0.606). Further to assess the immunological memory produced by this new regimen, a "single visit four site" intradermal booster vaccination was given to those who did not have adequate RVNA concentration on day 365. This resulted in a quick and enhanced RVNA concentration in these subjects thus denoting a successful anamnestic response. The incidence of adverse events was 8.3% in PCECV group and 1.6% in PVRV group (P=0.001) and the regimen was well tolerated without any dropouts. In conclusion, the new "one week intradermal regimen" is immunogenic and safe for rabies post-exposure prophylaxis and needs to be further evaluated in persons exposed to rabies.

Immunogenicity, safety and tolerance of a purified duck embryo vaccine (PDEV, VAXIRAB) for rabies post-exposure prophylaxis: Results of a multicentric study in India.

Rabies continues to be a major public health problem in India. Nearly 17 million people are getting exposed to this disease every year. Therefore the need for effective post-exposure prophylaxis with safe and potent modern rabies vaccines continues to exist. Purified Duck Embryo Vaccine (PDEV) was introduced in this country to meet the ever increasing need for modern rabies vaccines. In this study we have assessed the safety, imunogenicity and tolerance of an indigenously manufactured PDEV in people exposed to dog and other animal bites. One hundred and fifty people (5-59 years) who were having WHO category II or III animal bites were vaccinated with PDEV using the Essen Intramuscular regimen and rabies immunoglobluin (RIG) was administered to category III exposures. Their blood samples were analyzed for rabies virus neutralizing antibody response (RVNA) by Rapid Fluorescent Focus Inhibition Test (RFFIT) on day 0, 14, 30, 90, 180 and 365. Adverse effects to vaccines were monitored during the course of vaccination. There was 100% sero-conversion from day 14 onwards with adequate RVNA titers (>=0.5 IU/mL) up to day 365. The incidence of side effects was minimal and self limiting. Hence it can be concluded that indigenously manufactured PDEV (Vaxirab) is a safe and immunogenic vaccine and can safely be used for post-exposure prophylaxis.

Immunogenicity and safety study of Indirab: a Vero cell based chromatographically purified human rabies vaccine.

A chromatographically purified Vero cell rabies vaccine, Indirab manufactured by Bharat Biotech International Limited, Hyderabad, India was subjected to safety and immunogenicity studies by both intramuscular and intradermal routes of administration in parallel with a reference vaccine, Verorab. A Pre-exposure study was undertaken in 239 subjects by intramuscular (IM) route (Study I), Post-exposure study in 188 patients by intramuscular route (Study II) and Simulated post-exposure study in 134 subjects by intradermal (ID) route (Study III). All subjects in these studies were administered with either the test or the reference vaccine as per WHO approved intramuscular and intradermal regimens. The blood samples were collected on days 0, 14 and 35 in case of Study 1, and days 0, 14, 28 and 90 in case of studies II and III. In all studies both vaccine groups had adequate antibody titers (>0.5 IU/mL) on all days tested post-vaccination and there was no significant difference in the titers observed (p>0.05). Some side effects like pain, induration, itching and fever were noted in both vaccine groups in all studies. Both vaccines were well tolerated. Hence it can be concluded that Indirab is as safe and immunogenic as Verorab when administered by both intramuscular and intradermal routes.

A comparative study on the safety and immunogenicity of Purified duck embryo vaccine [corrected] (PDEV, Vaxirab) with purified chick embryo cell vaccine (PCEC, Rabipur) and purifed vero cell rabies vaccine (PVRV, Verorab).

Rabies is a fatal but preventable disease. Cell culture vaccines (CCV) and purified duck embryo vaccines (PDEV) are currently recommended by WHO for post-exposure prophylaxis. In India, a PDEV (Vaxirab) is being manufactured and is in use since 2003. In the present study, we have evaluated the safety, immunogenicity and tolerance of this vaccine with two other WHO approved CCVs, viz., purified chick embryo cell vaccine (PCEC, Rabipur) and purified vero cell rabies vaccine (PVRV, Veroroab). This study was an open label, randomized phase IV comparative clinical trial. A total of 152 people bitten by dogs and other animals were recruited from 4 different centres from India. They were randomly assigned to receive one of the vaccines by Essen intramuscular regimen (52 subjects received Vaxirab and 50 each Rabipur and Verorab) and rabies immunoglobulin was also administered in all category III exposures. Their blood samples were collected on day 0 (prior to vaccination), 14, 28, 90 and 180. Side effects if any were monitored. The rabies neutralizing antibody titers in their blood samples were estimated by the rapid fluorescent focus inhibition test (RFFIT). Subjects in all three groups had neutralizing antibody titers by day 14 (>0.5 IU/mL) and geometric mean titers (GMT) observed for different vaccines on all days tested did not vary significantly (p>0.5). Side effects observed were minimal and did not vary significantly among the groups. The results of the present study indicate that PDEV (Vaxirab) is as safe, tolerable and immunogenic as both PCEC (Rabipur) and PVRV (Verorab). Thus this vaccine can be a good alternative to WHO approved CCVs for rabies post-exposure prophylaxis.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): a randomized simulated post-exposure study in healthy volunteers.

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.