Last week, the French vaccine maker Valneva announced promising phase III trial results of its inactivated Covid-19 vaccine: a well-established technology that could confer broader immunity to the virus than shots currently on the market.
Valneva’s vaccine candidate consists of a killed or ‘inactivated’ version of SARS-CoV-2, the virus responsible for Covid-19. The vaccine was tested in adults aged 18 and up in a phase III trial and its protection was compared to AstraZeneca’s Covid-19 vaccine.
According to the trial results, participants treated with Valneva’s candidate experienced fewer side effects than those given AstraZeneca’s vaccine, particularly those over 30. Additionally, the group given Valneva’s candidate carried more neutralizing antibodies against SARS-CoV-2 in their blood.
Covid-19 vaccines currently on the market in Europe are based on either adenoviral vectors, including vaccines from AstraZeneca and Johnson & Johnson, or newer messenger mRNA (mRNA) technology including vaccines from BioNTech/Pfizer and Moderna. Their exclusive target is the spike protein on the surface of the virus, which the virus uses to enter cells. However, the protein mutates much more quickly than other parts of the virus, which increases the likelihood of the virus becoming resistant to the vaccine.
Inactivated vaccines like Valneva’s candidate allow the immune system to target a wider range of viral proteins than approved vaccines, which could make them harder for the virus to resist.
“Inactivated vaccines are a well-established technology used over the last 100 years to vaccinate billions – including for seasonal flu, hepatitis A, polio, and rabies,” Valneva’s CMO, Juan Carlos Jaramillo, told me. “In an inactivated vaccine, the virus is killed but the whole virus envelope is preserved so compared to vaccines targeting only the spike protein, inactivated vaccines have the potential to provide an added benefit by boosting T-cell responses against additional SARS-CoV-2 proteins.”
While about 75% of eligible adults across Europe have been fully vaccinated to date, emerging virus variants and the side effects of this first generation of Covid-19 shots have fueled a race to bring to market better vaccines.
Valneva has already filed for initial approval of its candidate with the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and is about to apply with the European Medicines Agency (EMA). The candidate will join four other vaccines under rolling review by the EMA, including two protein vaccines, Russia’s adenoviral vector vaccine Sputnik V, and Sinovac’s Vero Cell, which also uses a dead whole virus.
The positive phase III results have seen Valneva’s stock price rise by over 60% since last week. They come two months after the phase III success of Valneva’s vaccine for chikungunya, and just over a month after the UK government unexpectedly scrapped a Covid-19 vaccine supply agreement with Valneva, causing the company’s stock price to plummet by 40%. The UK’s Health Secretary said at the time that the vaccine wouldn’t have gained UK approval, though reasons for this statement were not provided.
Other approaches to boosting Covid-19 immunity include viral protein vaccines, such as the candidates under review by the EMA produced by US-based Novavax and a partnership between Sanofi-Pasteur and GSK, and vaccines made from DNA, including one that was approved in India earlier this year. In addition, a number of oral and nasal Covid-19 vaccine candidates, which claim to boost immunity at the site of entry of the pandemic virus, are in different stages of development around the globe.
According to Valneva’s phase III results, those given Valneva’s vaccine had the same risk of Covid-19 infection as those given AstraZeneca’s vaccine, and there were no severe cases in either group. However, this trial differed from those of BioNTech/Pfizer and other Covid-19 vaccine frontrunners by focusing on proxy measures such as blood antibody levels as its main success indicator rather than the number of infection cases. Many scientists consider these to be satisfactory surrogate endpoints for emergency authorization.
“This trial design of comparative immunogenicity, if sufficiently powered, is still rigorous, and likely something we will see going forward for Covid-19 and for other infectious diseases with an established standard of care,” said Jose Ordovas-Montanes, an immunologist at Harvard University who is not affiliated with the trial. “Of course, and this is a big point, the ultimate test is still a trial of efficacy with sufficient patient numbers enrolled and duration to evaluate the number of positive cases, viral loads, and symptoms in individuals that are infected by SARS-CoV-2 enrolled in the trial.”
An efficacy trial would be particularly important in evaluating claims that novel vaccines offer broader immunity than the ones currently on the market, Ordovas-Montanes added. The FDA and EMA are beginning to open the way for booster doses of current Covid-19 vaccines, and any newer vaccines need to prove their worth in populations that have either recovered from Covid-19 or have been already vaccinated.
“It very well could be that a mix-and-match booster approach to broaden the response to other parts of the virus beyond the spike protein could be efficacious to stimulate other arms of the immune response more effectively, or prevent immune evasion of variants that mutate spike,” said Ordovas-Montanes.
Cover image via Anastasiia Slynko