COVID-19 vaccines: early success and remaining challenges

The Lancet
Sep 05, 2020 Volume 396 Number 10252 p649-734, e22-e24


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COVID-19 vaccines: early success and remaining challenges
Naor Bar-Zeev,
Tom Inglesby
…The two studies by Logunov and colleagues have several strengths. First, adenoviruses are ubiquitous, so humans might not be immunologically naive. Previous immunity to the vector might interfere with adenovirus-vectored COVID-19 vaccine efficacy. Indeed, findings of an adenovirus type 5-vectored COVID-19 vaccine trial suggested such immunity could affect COVID-19 responses.2 In another study, a chimpanzee adenovirus vector was used, since humans will presumably be naive to at least the first dose.3 Logunov and colleagues used immunologically distinct (heterologous) vectors in their two-dose (prime-boost) regimen. They investigated cross-vector heterologous immunity and previous antivector adenovirus immunity, and neither affected COVID-19 immunogenicity.

A second strength is the threshold for neutralisation used in the two studies. Neutralisation assays vary from study to study. Neutralisation is tested by examining whether plasma from a recently vaccinated individual can prevent cellular damage on in-vitro exposure of cells to SARS-CoV-2. Both the degree of such protection (how many damaged cells are allowed) and the dose of the infecting virus vary across studies. Expecting a vaccine to result in less than complete neutralisation is not inherently wrong but sets the bar low and makes it easier to claim neutralising activity. In Logunov and colleagues’ studies, however, the threshold for neutralisation was set high in two regards: the inoculating viral dose was large, and no arising cellular damage was allowable. Essentially, the assay was set at full neutralisation. This high bar implies these researchers took an a-priori risk that their vaccine might fail the test. It did not. It remains to be seen if other manufacturers will set a similar high standard.

A third strength is that the vaccine, similar to other adenovirus-vectored and mRNA COVID-19 vaccines before it,2  34 induced broad immune responses. Although not specifically discussed, the results imply a T-helper-1-cell-weighted response that might be important for vaccine safety, potentially reducing the risk of antibody-dependent enhanced disease.5

A fourth strength was development of two vaccine formulations, frozen and lyophilised. A lyophilised formulation could mean stability within the existing global vaccine refrigerated cold chain that is needed to maintain vaccine efficacy from factory to recipient, a hurdle other vaccines are yet to address. Although more costly to produce at scale, product stability will maximise reach in remote terrain, a must if universal and equitable coverage is to be achieved.

Some limitations of the studies by Logunov and colleagues are notable. In the study of the frozen vaccine formulation, the population included young military personnel. Soldiers are likely to be fitter and healthier than the general population. Moreover, in older adults, immune senescence might make vaccines less immunogenic, and this age group was absent from this study. Sex imbalance occurred in the study arms because there was no random allocation. A control arm was conspicuously absent. Two participants were of Asian descent, with the rest of the participants of white European ethnic origin. Clearly, much more remains to be learned from the phase 3 randomised trial planned to include 40 000 civilian volunteers and, hopefully, broadly inclusive of groups at risk…