Optimism and caution for an inactivated COVID-19 vaccine
Authors: Christina A Rostad, Evan J Anderson
Journal: The Lancet Infectious Diseases (2021)

Although the COVID-19 pandemic has caused substantial morbidity, mortality, and social upheaval worldwide, the final months of 2020 heralded the high efficacy and safety results of three phase 3 clinical trials of SARS-CoV-2 vaccines.1Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; (published online Dec 10.)https://doi.org/10.1056/NEJMoa2034577Crossref Scopus (9494) Google Scholar, 2Jackson LA Anderson EJ Rouphael NG et al.An mRNA vaccine against SARS-CoV-2 - preliminary report.N Engl J Med. 2020; 383: 1920-1931Crossref PubMed Scopus (2269) Google Scholar, 3Voysey M Clemens SAC Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2020; (published online Dec 8.)https://doi.org/10.1016/S0140-6736(20)32661-1Summary Full Text Full Text PDF Scopus (3258) Google Scholar, 4Baden L El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2020; (published online Dec 30.)https://doi.org/10.1056/NEJMoa2035389Crossref Scopus (6547) Google Scholar The first COVID-19 vaccine to be approved in the western world, BNT162b2 (Pfizer),1Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; (published online Dec 10.)https://doi.org/10.1056/NEJMoa2034577Crossref Scopus (9494) Google Scholar was closely followed by mRNA-1273 (Moderna),2Jackson LA Anderson EJ Rouphael NG et al.An mRNA vaccine against SARS-CoV-2 - preliminary report.N Engl J Med. 2020; 383: 1920-1931Crossref PubMed Scopus (2269) Google Scholar and the chimpanzee-adenovirus vectored AZD1222 (AstraZeneca–Oxford).3Voysey M Clemens SAC Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2020; (published online Dec 8.)https://doi.org/10.1016/S0140-6736(20)32661-1Summary Full Text Full Text PDF Scopus (3258) Google Scholar Unfortunately, cold-chain requirements, finite global manufacturing capacity, and insufficient supply are likely to disproportionately affect low-income and middle-income countries (LMICs). Although multilateral agreements have been made to purchase vaccines for LMICs through the COVID-19 Vaccine Global Access Facility, a global collaboration established to provide equitable access to COVID-19 vaccines, only enough doses to vaccinate 250 million people have been purchased to date. Mathematical models indicate there will not be an adequate supply of vaccines available to cover the global population until 2023,5McDonnell A Van Exan R Lloyd S et al.COVID-19 Vaccine predictions: using mathematical modelling and expert opinions to estimate timelines and probabilities of success of COVID-19 vaccines. Center for Global Development, Washington, DCOctober, 2020https://www.cgdev.org/publication/covid-19-vaccine-predictionsDate accessed: December 11, 2020Google Scholar further exacerbating health and other disparities in LMICs. Thus, the early safety and immunogenicity results from Raches Ella and colleagues published in The Lancet Infectious Diseases6Ella R Vadrevu KM Jogdand H et al.Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial.Lancet Infect Dis. 2021; (published online Jan 21.)https://doi.org/10.1016/S1473-3099(20)30942-7Summary Full Text Full Text PDF PubMed Scopus (278) Google Scholar of BBV152, a SARS-CoV-2 vaccine manufactured and produced in India by Bharat Biotech, are a welcome addition to the COVID-19 vaccine landscape. Bharat Biotech, experienced with developing and distributing vaccines to LMICs, is poised to bridge the vaccine disparity gap using the well established inactivated whole-virus vaccine platform. In a multicentre, double-blind, randomised phase 1 trial, investigators enrolled 375 healthy adults in India, who were assigned to receive two doses separated by 2 weeks of BBV152 3 μg with Algel-IMDG (n=100), 6 μg with Algel-IMDG (n=100), or 6 μg with Algel (n=100), or an Algel-only control (n=75). Researchers found the vaccine to be safe and less reactogenic than reported with BNT162b21Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; (published online Dec 10.)https://doi.org/10.1056/NEJMoa2034577Crossref Scopus (9494) Google Scholar and mRNA-1273.2Jackson LA Anderson EJ Rouphael NG et al.An mRNA vaccine against SARS-CoV-2 - preliminary report.N Engl J Med. 2020; 383: 1920-1931Crossref PubMed Scopus (2269) Google Scholar They found that more than 80% of patients in each vaccine group seroconverted, with at least a four-fold increase in binding antibody titres. Seroconversion occurred by microneutralisation in 88% in the 3 μg Algel-IMDG group and 92% in the 6 μg with Algel-IMDG group, but also in 8% of participants in the control group, suggesting SARS-CoV-2 infections occurred in some participants. Algel-IMDG groups achieved similar microneutralisation titres compared to a panel of convalescent SARS-CoV-2 sera (25 from symptomatic individuals and 16 from asymptomatic individuals; severity not reported). The ability to interpret the potential immunogenicity and efficacy of BBV152 by comparison with other advanced vaccine candidates is limited by the absence of SARS-CoV-2 standardised reference assays and established correlates of protection. Despite these favourable phase 1 results, concerns linger regarding the potential for an inactivated whole-virus vaccine to elicit antibody-dependent enhancement of infection or vaccine-associated enhanced respiratory disease upon SARS-CoV-2 infection.7Graham BS Rapid COVID-19 vaccine development.Science. 2020; 368: 945-946Crossref PubMed Scopus (518) Google Scholar Both of these effects are thought to be attributable to the development of binding, poorly neutralising antibodies that can promote either enhanced infection of Fc-bearing immune cells or immune complex deposition with T-helper-2 cell-biased allergic inflammation. In-vitro studies and some small animal model studies with other coronaviruses have raised concern about antibody-dependent enhancement of infection and vaccine-associated enhanced respiratory disease, but to date, neither have been observed in SARS-CoV-2 vaccine clinical trials. The inactivated platform raises concern, because inactivation might alter antigenic structures and thereby elicit binding, non-neutralising antibodies. Thus, achieving high titres of neutralising antibodies and T-helper-1 (Th1)-biased cellular responses are considered important safety metrics in the assessment of candidate vaccines. In the study by Ella and colleagues,6Ella R Vadrevu KM Jogdand H et al.Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial.Lancet Infect Dis. 2021; (published online Jan 21.)https://doi.org/10.1016/S1473-3099(20)30942-7Summary Full Text Full Text PDF PubMed Scopus (278) Google Scholar they address potential concerns for antibody-dependent enhancement of infection and vaccine-associated enhanced respiratory disease. BBV152 was adjuvanted with the toll-like receptor 7/8 agonist imidazoquinoline, a potent immunostimulatory molecule that biases towards Th1 activation and antibody production. Although not yet published in peer-reviewed journals, preclinical studies of BBV152 in hamsters8Mohandas S Yadav P Shete A et al.Immunogenicity and protective efficacy of BBV152: a whole virion inactivated SARS-COV-2 vaccine in the Syrian hamster model.Res Square. 2020; (published online Sept 16.) (preprint)https://doi.org/10.21203/rs.3.rs-76768/v1Google Scholar and rhesus macaques9Yadav P Ella R Kumar S et al.Remarkable immunogenicity and protective efficacy of BBV152, an inactivated SARS-CoV-2 vaccine in rhesus macaques.Res Square. 2020; (published online Sept 10.)https://doi.org/10.21203/rs.3.rs-65715/v1Google Scholar showed that the vaccine elicited high titres of neutralising antibodies and protected against SARS-CoV-2 challenge without evidence of enhanced respiratory disease. Ella and colleagues also found that IgG1/IgG4 ratios were greater and IFN-γ CD4+ and CD8+ cells were present in participants who received Algel-IMDG, suggesting that Algel-IMDG stimulated a Th1-biased response. Still, questions remain: Will BBV152 be efficacious? Is IMDG sufficient to subvert a Th2 response? Will enhanced disease occur? These questions might only be answered in a more diverse multinational phase 3 trial, which must comprehensively assess efficacy and long-term safety. Until then, we will wait with cautious optimism on this vaccine candidate poised to bolster worldwide equitable access to COVID-19 prevention. CAD and EJA have received federal funding from the National Institute of Allergy and Infectious Diseases to their institution to conduct phase 1 and 3 clinical trials in adults. CAR's institution has received funds to conduct clinical research unrelated to this manuscript from BioFire, MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi-Pasteur, Janssen, and Micron. She is also co-inventor on patented respiratory syncytial virus vaccine technology unrelated to this manuscript, which has been licensed to Meissa Vaccines. EJA has received personal fees from AbbVie, Pfizer, and Sanofi Pasteur for consulting, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trialBBV152 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. Full-Text PDF