By Paul A. Offit, M.D.

In November 2019, a bat coronavirus made its debut in humans in Wuhan, China. Two months later, the original strain of SARS-CoV-2, called the Wuhan-1 or ancestral strain, was isolated and sequenced. It was now possible to make a vaccine. All the vaccines, including the mRNA vaccines made by Pfizer–BioNTech and Moderna, the viral vector vaccines made by Johnson & Johnson–Janssen and AstraZeneca, and the purified protein vaccine made by Novavax, were designed to prevent disease caused by the ancestral strain.

As the virus evolved, the ancestral strain was soon replaced by a series of variants. In the United States in 2020 and 2021, such variants included D614G, alpha, and delta, each of which was more contagious than the previous variant. In a U.S. study involving 8100 immunocompetent adults conducted between March and December 2021, two doses of mRNA vaccines — which were authorized by the Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) in December 2020 — continued to protect against hospitalization caused by these three virus variants.1 For vaccines against SARS-CoV-2, a mucosal infection with a short incubation period, protection from severe disease is the only reasonable and attainable goal.

In November 2021, a new variant, called omicron (subvariant BA.1), was detected in southern Africa. The omicron variant contained an alarming number of mutations (more than 30) in the spike protein, including at least 15 mutations in the receptor-binding domain, the primary target of neutralizing antibodies. Researchers found that serum samples obtained from people who were vaccinated against or previously infected with SARS-CoV-2 exhibited substantially lower neutralizing activity against BA.1 than against the ancestral strain and other strains. Furthermore, many commercially available monoclonal-antibody preparations were ineffective against this variant. Although it was reassuring that early data from southern Africa showed that previous infection or vaccination protected against severe disease caused by omicron,2 public health officials worried that the BA.1 strain posed a serious threat to the effectiveness of existing Covid-19 vaccines and therapies.

Given the ability to use mRNA technology to respond quickly to variant strains, bivalent vaccines were created to counter this new threat. In January and February 2021, Pfizer–BioNTech produced a bivalent vaccine containing 15 μg of mRNA directed against the ancestral strain of SARS-CoV-2 and 15 μg directed against BA.1. Moderna used 25 μg of mRNA directed against each of the same two strains. The combined quantities mirrored the amount of mRNA in each company’s monovalent booster dose for adults (30 μg for Pfizer–BioNTech and 50 μg for Moderna).

Continue reading article in The New England Journal of Medicine by Paul Offit

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