И Ланцет сразу опубликовал с комментарием двух авторов из Джона Хопкинса:
In The Lancet, Denis Y Logunov and colleagues from the N F Gamaleya Research Institute of Epidemiology and Microbiology in Russia present findings from two phase 1/2, non-randomised, open-label studies of a heterologous, replication-deficient, recombinant adenovirus vector-based vaccine in both frozen and lyophilised formulations.1 The researchers enrolled 76 healthy adult volunteers (aged 18–60 years) into the two studies (38 people in each study); 53 (70%) participants were men and 23 (30%) were women.
Хвалят по ряду позиций саму вакцину, принцип построения:
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.
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.
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 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.
A fourth strength was development of two vaccine formulations, frozen and lyophilised.
- но и ожидаемо отмечают недостатки на этой фазе конкретных имеющихся исследований:
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.
This COVID-19 vaccine candidate from Russia joins two other adenovirus-vectored COVID-19 vaccine candidates, which have been reported in randomised trials in The Lancet, and an mRNA vaccine candidate reported in a non-randomised trial. Similar to these studies before it, Logunov and colleagues’ studies are encouraging but small. The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any COVID-19 vaccine has not yet been shown.
Showing safety will be crucial with COVID-19 vaccines, not only for vaccine acceptance but also for trust in vaccination broadly.6
Safety outcomes up to now are reassuring, but studies to date are too small to address less common or rare serious adverse events. Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the COVID-19 pandemic, potentially to everyone after approval following phase 3 trials, safety is paramount.
Licensure in most settings should depend on proven short-term and long-term efficacy against disease (not just immunogenicity) and more complete safety data, including rates of vaccine failure to prevent infection (not merely disease) and rates of occurrence of antibody-dependent enhanced disease, ideally from very large scale, flexible multivaccine trials with prolonged, blinded safety and efficacy follow-up.
Safety assurance will then require further large-scale surveillance after licensure.
Важный неочевидный момент отмечают:
Surveillance will also be vital for showing transmission reduction, which is unlikely to come from phase 3 trials since these are powered to detect COVID-19 disease outcomes and not asymptomatic SARS-CoV-2 infection.
To be sure, most past vaccines were designed to target disease and not infection as such, but with COVID-19, the general public could be expecting striking reductions in disease transmission after widespread vaccine introduction.
Such effects would be very welcome if they occur, but they are far from certain. A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission-mitigating behaviours.