The COVID-19 pandemic has led to intensive scientific efforts to bring about an effective vaccine for global distribution. Many different vaccine design approaches are underway. A recent study published in the journal The Lancet Infectious Diseases in October 2020 reports a potentially successful inactivated virus vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The ongoing COVID-19 pandemic is the only outbreak to date in which the time from identification of a pathogen to the presentation of the first clinical trial results for a specific vaccine against the pathogen was less than nine months. By September 2020, over 39 vaccine candidates have already begun to be tested, with more than 200 more in preclinical development.
The preliminary data on these vaccine trials is vital in understanding how safe and effective the vaccines are likely to be, given that they are designed to counter a novel virus and that many adverse effects may be found only by observation rather than by prediction.
Whole Virus Vaccine
One study of a recently tested inactivated beta-propiolactone aluminum hydroxide-adjuvanted whole-virion SARS-CoV-2 vaccine candidate by Chinese researchers has been published. The trial was a randomized controlled double-blinded, phase ½, in healthy adults. Including people over 60 years, this was a pioneering trial in offering evidence of vaccine effects on older people for the first time among all inactivated SARS-CoV-2 trials.
The vaccine was given in the classic prime-boost format, at three different concentrations, in phase 1, using a dose-escalating protocol. The doses used were 2 μg, 4 μg, and 8 μg,
Immunogenicity and Safety in Older Individuals
The investigators found high tolerability in both the age groups of 18-59 years and 60 years and over. The rates of adverse events were lower in the latter group, at 47% of 72 younger participants having reported adverse events within 28 days of vaccination, compared to ~20% of an equal number of individuals aged 60 or more.
Immunogenicity was comparable in both groups, as measured by the geometric mean titers during a 50% virus neutralization assay at 14 days after the booster dose.
The researchers also looked for cross-reactivity, finding that the neutralizing antibodies could continue to be effective despite some degree of drift, promising to cover divergent strains if they should emerge in the community.
Optimal Prime-Boost Delay
In phase 2, the early part of the trial looked at the effects of using a prime-boost protocol with only 14 or 21 days between the two doses, rather than 28 days. The researchers noted that at an interval of 21 days from prime to boost, the vaccine's 4 μg dose elicited the highest immune response. When the interval was shortened, the immunogenicity was markedly less.
Implications and Future Directions
The results confirm an earlier Wuhan study using the same type of inactivated virus particle to neutralize antibody titers and adverse events. This indicates that the efficacy of the vaccine is preserved even when made by different manufacturers. The efficacy of the whole-virus particle may be due to the presence of all the epitopes.
However, the study also shows that it is possible to stabilize the structure of the major antigens. The use of appropriate inactivation methods is crucial to preventing the induction of non-neutralizing and possibly harmful antibodies by altered epitopes. The current study showed no evidence of disease enhancing effects in various animal models, secondary to vaccination-induced antibodies, following exposure to the virus.
The study is not conclusive since more detailed and long-term monitoring in a broader range of animal models is necessary to explore such antibody-dependent enhancement phenomena. A second area to be investigated is whether the vaccine elicits specific and durable CD4+ T cell responses since these are necessary for optimal antibody generation as well as for cytotoxic CD8+ T cell activation, needed for viral clearance in the event of incomplete neutralization by antibodies.
The vaccine is currently undergoing phase 3 testing for its safety and efficacy and the duration of protection. It is expected that this will contribute to the sum of knowledge about the protective effects of inactivated SARS-CoV-2 vaccines.
Isakova-Sivak, I. A Promising Inactivated Whole-Virion SARS-Cov-2 Vaccine. The Lancet Infectious Diseases. DOI:https://doi.org/10.1016/S1473-3099(20)30832-X. https://www.thelancet.com/journals/lanpsy/article/PIIS1473-3099(20)30832-X/fulltext