Interim phase III data on Sputnik V, the adenovirus-based Covid-19 vaccine developed at the Gamaleya Research Institute in Russia, were reported in the Lancet today and look solid at first glance, with a respectable efficacy rate of 91.6%.
But two deaths associated with Covid-19 among the vaccine recipients might raise concerns, though the researchers insisted that these were due to pre-existing conditions, and that the patients had been infected before they were dosed. Other intriguing aspects are the use of different adenoviral vectors for the two doses, and the storage requirements for the vaccine, which might be more onerous than expected.
Of the participants in the Resist trial, 16 of the 14,964 vaccine recipients and 62 of those given a placebo contracted the virus. The time point at which this was assessed was unusually strict: 21 days from the first dose, ie the date of the second dose. Pivotal studies of the other prime-boost vaccines that have reported data left at least a week after the second dose for immunity to develop before assessing efficacy.
Crucially, there were no cases of moderate or severe Covid-19 in the treatment group, versus 20 with placebo. Safety was clean, with no vaccine-related serious adverse events.
But the deaths might rankle. They were caused by cardiovascular and endocrine conditions exacerbated by Covid-19, the authors said. More importantly, the two subjects died four and five days after their first doses, allowing the researchers to conclude that they had already been infected before being included in the study, despite negative PCR tests at enrolment.
There have been no Covid-19 deaths with the other vaccines on which phase III data have been reported.
|Vaccine efficacy comparison|
|Covid-19||Severe Covid-19||Covid-19 death|
|Johnson & Johnson||Ad26.COV2.S/
|66% effective||66%||85% effective||0||Unknown|
|*Moderate to severe cases. **Infections judged to predate vaccination. Source: company releases, the Lancet, the NEJM.|
One intriguing aspect of Sputnik V is that it uses two different adenoviruses: the first dose is based on recombinant Ad26 and the second, 21 days later, on rAd5, with both vectors carrying the gene for the full-length spike protein.
The authors wrote that using a different vector for the booster might help create a more powerful immune response than using the same vector twice – as Astrazeneca’s vaccine does, for instance – as this minimised the risk of the immune system developing resistance to the initial vector.
A question for the future is what this means for redosing after a longer interval, such as for an annual booster. If recipients become less responsive to adenoviral vectors, will new vectors have to be found for each additional shot? Or will immunity to the vectors wane along with immunity to the coronavirus, allowing their reuse?
Other questions are also pressing. The Lancet paper did not include any data on the vaccine’s effectiveness against new variants of the coronavirus, so further trials will be needed to tease this out.
And vaccine watchers will note that Sputnik V appears more effective than the other vaccines that can be stored conveniently in fridges – those from Astrazeneca, Novavax and Johnson & Johnson. But this is not in fact the case. The vaccine used in the Resist trial was in fact a liquid formulation that requires storage at -18°C, so in storage terms the vaccine used in the trial is more similar to the mRNA vaccine from Moderna, whose efficacy was 94%.
The freeze-dried form of Sputnik V that can be stored in a fridge is approved by Russia’s Ministry of Health, but there do not seem to be any concrete phase III data backing it.
These issues will soon come under scrutiny by EU regulators; an MAA for the vaccine is expected to be filed this month. Sputnik V is already authorised for use in 16 countries, including Hungary, Belarus and Argentina, as well as in Russia itself, which approved the vaccine last August on the strength of phase II data.