Optimism and caution for an inactivated COVID-19 vaccine.

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.1, 2, 3, 4 The first COVID-19 vaccine to be approved in the western world, BNT162b2 (Pfizer), was closely followed by mRNA-1273 (Moderna), and the chimpanzee-adenovirus vectored AZD1222 (AstraZeneca–Oxford).

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, 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 Diseases 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 BNT162b2 and mRNA-1273. 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. 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, 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 hamsters and rhesus macaques 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.