A COVID-19 booster that targets two versions of the coronavirus at once provided stronger and broader protection than the current booster, which targets just one version, according to clinical trial results released this week by vaccine maker modern.
The results are preliminary and have not been peer-reviewed or published in a scientific journal. But Moderna touted the findings as evidence that bivalent or multivalent vaccines — those that target two or more versions of the virus at once — are the way forward for COVID-19 boosters.
Moderna and other vaccine makers are on a mission to develop boosters that could restore the once extraordinarily high levels of protection initially provided by mRNA-based COVID-19 vaccines, while also protecting against future variants. The first-generation mRNA vaccines were all designed to target the ancestral version of SARS-CoV-2 isolated in Wuhan, China — and they did so quite effectively, with efficacy against symptomatic diseases in the margin of 95 per cent. But the virus has evolved into variants that can evade vaccine-derived protections. The latest variant, omicron, significantly reduced the vaccine’s effectiveness against symptomatic diseases, although protection against serious diseases remains strong. Booster doses of the current vaccine design provide protection, but do not restore the high levels seen before. And the virus continues to evolve.
That’s why vaccine makers are testing variant-specific boosters and combination shots. Moderna and Pfizer/BioNTech — joint makers of the other leading mRNA COVID-19 vaccine — quickly announced plans for an ommicron-specific vaccine in December, before the rapidly evolving variant swept the world. But so far, early animal data has suggested that a booster dose targeting only the omicron variant may not provide an advantage over current vaccines in protecting against omicron. While data on variant-specific vaccine studies is still coming in, vaccine makers have also been working on combination shots. For example, earlier this month, the National Institutes of Health announced the start of a clinical trial (in partnership with Moderna) that will test six different booster regimens, four of which involve a combination injection.
New data
Moderna now has data on one of its first combination shots, which targets the ancestral tribe plus the beta variant. The beta variant was first identified in South Africa and was named a “variant of concern” in December 2020 after it was shown to be able to evade vaccine-derived immune responses. Although experts initially feared it would trigger an ommicron-like spate of infections, beta never became widespread in the US and has since been completely displaced by omicron.
Still, vaccine makers had begun work on beta-targeted vaccines last year. And that work has now proved somewhat helpful, as beta shares some of the key mutations for evading protective antibodies found in ommicrons. Thus, combination vaccines targeting beta may foreshadow benefits that combination vaccines targeting ommicron may have in the future.
The new data released by Moderna looked at neutralizing antibody levels in about 300 people who received a 50 microgram dose of the beta/ancestral combo vaccine (called mRNA-1273,211). The antibody levels in that group were compared with those of about 150 people who received the current 50 microgram booster (mRNA-1273) that targets the ancestral version of the virus. Compared to the current booster, the beta/ancestral combo injection generated higher levels of neutralizing antibodies against the ancestral virus, as well as the beta, omicron, and delta variants. In the case of omicron, the combo injection generated neutralizing antibody levels twice as high as the current injection (when comparing geometric mean titers). That double benefit was maintained even after six months. Furthermore, there were no safety concerns with the combination vaccine during the trial and the side effect profile looked similar to that of the current booster.
fall strategy
Of course, this research has limitations. The number of people in the trial was not huge, and the study is not large enough to look at the vaccine’s effectiveness. The study also doesn’t look at other types of immune responses, such as cell-based responses. But it strongly suggested that a bivalent vaccine could outperform the current vaccine, as neutralizing antibody levels tend to correlate with protection. The study authors speculated that the additional virus targets present in the combination vaccine induce “further maturation and evolution” of antibody responses in vaccinated humans. “Therefore, immunization with the primary series does not cap the neutralizing antibody response,” they wrote, “and a booster dose of the bivalent vaccine elicits a robust response with titers likely to be protective against COVID-19.”
In a statement, Moderna’s CEO, Stéphane Bancel, said the findings boosted the company’s optimism for combination shots. “We believe these results validate our bivalent strategy, which we announced and began pursuing in February 2021. The results indicate that mRNA-1273,211 [the combo shot] at the 50 µg dose level induced higher antibody responses than the 50 µg mRNA-1273 [current] booster, even when additional variants of concern were not included in the booster vaccine,” Bancel said.
With their strategy for future boosters, Moderna expects to deliver newly formulated boosters before the fall. However, Bancel expects an ommicron/ancestral combo booster to provide even stronger, broader protection.
“Our newest bivalent booster candidate, mRNA-1273,214, which combines the currently authorized Moderna COVID-19 booster with our ommicron-specific booster candidate, remains our lead candidate for the Northern Hemisphere booster in the fall of 2022,” Bancel said. “We look forward to sharing initial data on mRNA-1273,214 later in the second quarter. We believe that a bivalent booster vaccine, if authorized, would create a new tool as we continue to respond to emerging variants.”
