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A vaccine adapted to fight the Beta variant tested on animals

The reasons for the continuation of the pandemic include insufficient vaccination coverage, the weakening of antibody protection over time, and the emergence of variants of concern (VOCs) that are more resistant and that have increased transmissibility. Moderna has recently produced a vaccine (mRNA-1273.β)  “tweaked” to adapt to the Beta (South African) variant, one of the VOCs that is most resistant to neutralisation. In vitro studies have shown that the tweaked vaccine induces greater numbers of neutralising antibodies that are also more effective against all variants. However, results exist only for in vivo tests.

To remedy this situation, American researchers at the National Institute of Health (NIH, Bethesda) vaccinated rhesus macaques with Moderna vaccines (2 doses at an interval of 4 weeks), then evaluated the effects of a 3rd dose on protection against the Beta VOC. Throughout the procedure, the immune response was evaluated using blood, bronchoalveolar or nasal samples. The results showed that the “classic” Moderna vaccine produces high levels of anti-spike antibodies in the blood and in the respiratory passages. But 6 months later, levels fell 4-fold against the Wuhan strain and 6-fold against Beta. The level of Wuhan- and Beta-specific B-memory cells (double reactivity) dropped 10-fold. However, antibody affinity maturation continued, suggesting that the response against some VOCs evolves over time. Neutralisation of the Gamma, Iota, Delta and Beta VOCs fell 6-fold compared to D416G or Epsilon. However, if the primary vaccination is with the tweaked Moderna vaccine, the response against Beta is 4 times more effective.

Those animals vaccinated with the classic Moderna then received (6 months later) a 3rd dose of classic or tweaked Moderna. Two weeks later, levels of antibodies in the blood were the same as after vaccination: the level of neutralising antibodies increased 12-fold and were effective against all variants. The same pattern was observed in the respiratory passages. The level of double reactive (Wuhan + Beta) B memory cells was also restored, unlike levels of B memory cells specific to either Wuhan or Beta. T cell responses (Th1 and Tfh, but not Th2) were effectively reactivated.

Whether the 3 rd dose was the Moderna classic or tweaked version, the effects were the same. However, the Moderna classic produced antibodies more specific to the A site of the NTD ((N terminal domain) of the spike, whereas the tweaked Moderna tended to target the H site of the RBD (Receptor Binding Domain). When vaccination was carried out with the tweaked version of Moderna, with the 3rd dose being the classic version, the antibodies targeted the B,C,D and F sites of the RBD, unlike when all 3 injections used the tweaked version. 

Eight weeks after the 3rd injection, or 5 weeks after vaccination with the tweaked Moderna, the macaques were infected with the Beta VOC. Four days later, no infectious virus was detected in their lungs (except for one animal that had received 3 doses of the classic Moderna), in contrast to the non-vaccinated animals. Inflammation, pulmonary anomalies and the presence of viral proteins in the lungs were all reduced or non-existent. Seven days after infection, the infectious virus in the nasopharynx had diminished and it was detected in only 3/16 animals that had received 3 doses, a sign of much reduced transmission.

Following vaccination with the Moderna classic version, a booster injection 6 months later gave more effective protection against the Beta variant and provided wider and longer lasting immunity against VOCs. Even though the level of neutralising antibodies fell several months after vaccination, continued immunity maturation enabled the production of more effective antibodies against VOCs. It is precisely this B memory response that is reactivated and enlarged by the 3rd injection. However, primary vaccination with the tweaked Moderna vaccine generates a unique repertoire of effective antibodies against VOCs. The primary vaccination plays an essential role in the elaboration of a specific set of antibodies. This should be taken into account when devising vaccination strategy for naïve patients, according to the variants in circulation.

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