Highlights

Pfizer/BioNTech and Moderna have offered updated bivalent versions of their mRNA vaccines, Comirnaty and Spikevax.

The updated bivalent vaccines are indicated for booster vaccination to increase protection against the COVID-19 infection caused by the planet’s dominant Omicron variant of the SARS-CoV-2 coronavirus.

Updated bivalent vaccines, administered in a single dose, are approved for use by individuals (12 years of age or older for Comirnaty and 18 years of age or older for Spikevax) if at least 2 months have passed since the completion of the full primary vaccination or receipt of a booster dose of any approved COVID-19 vaccine.

The updated bivalent vaccines contain mRNA sequences encoding S proteins of the original nonmutant SARS-CoV-2 and its Omicron subvariants BA.4 and BA.5.

  • Comirnaty contains two mRNA sequences, tozinameran and famtozinameran, encoding the S antigen of the nonmutant SARS-CoV-2 and its Omicron subvariants BA.4/BA.5. Spikevax contains elasomeran and davesomeran.

Approval was granted by the U.S. Food and Drug Administration (FDA) in late August 2022.

 

Details

For each of the updated bivalent vaccines, the FDA’s verdict was based, first, on the extensive safety and efficacy data accumulated in clinical trials and clinical practice of the original monovalent vaccines, Comirnaty and Spikevax, second, safety and immunogenicity data collected in clinical trials of experimental mRNA vaccines from Pfizer/BioNTech and Moderna targeting the Omicron subvariant BA.1, third, preclinical data (animal studies) of bivalent vaccines.

The FDA, however, admits that it is not yet possible to accurately assess the actual protective efficacy of the updated vaccines adapted to Omicron. Assumptions that the vaccines will successfully prevent adverse outcomes (Omicron-induced severe COVID-19, hospitalization, or death) are based on neutralizing antibody titers (with no correlation to clinical benefit), and data on the duration of neutralizing antibody activity is limited to one month, with human evaluations conducted only for the Omicron subvariant BA.1.

The U.S. regulator has agreed with the overwhelming evidence that updated vaccines should mandatorily include the antigenic sequence of the original nonmutant coronavirus because the Omicron-only booster will not provide an immune response response with the proper broadness to cover other variants of coronavirus, since the Omicron variant is too antigenically distant from the original SARS-CoV-2.

Anyway, the way has been cleared for the rapid implementation into clinical practice of vaccines modernized according to the current mutational specificity of the SARS-CoV-2, which continues to evolve and acquire new mutations that allow it to evade the immune protection built by vaccines and/or COVID-19 infection.

In mid-August 2022, the United Kingdom became the first country in the world to approve an Omicron vaccine. The vaccine in question is mRNA-1273.214, a bivalent vaccine by Moderna called Spikevax bivalent Original / Omicron that combines mRNA sequences encoding S proteins of the original nonmutant SARS-CoV-2 coronavirus and its Omicron variant (B.1.1.529 [BA.1]). These single-stranded mRNA sequences are named elasomeran and imelasomeran, respectively.

vaccine
First Omicron Vaccine Appears

Spikevax bivalent Original / Omicron (elasomeran + imelasomeran; mRNA-1273.214) by Moderna is the world’s first vaccine to protect against the Omicron variant of the SARS-CoV-2 coronavirus.

It appears that the bivalent mRNA vaccines Comirnaty and Spikevax, adapted to the mutational features of the Omicron subvariants BA.4 and BA.4, will be distributed and used primarily in the United States, while other countries will receive mainly versions of these vaccines that take into account the specificity of the original Omicron BA.1. At any rate, the European Union, Switzerland, Australia and Canada have already done so with Spikevax. In Europe, the updated Comirnaty vaccine will first appear in a bivalent version with BA.1, then with BA.4 and BA.5.

 

Expert Comments

As of the end of August 2022, the Omicron subvariant BA.5 was the most common worldwide (except for a few countries). [1] [2] [3] [4] BA.5 and BA.4 introduced identical mutations in the S protein, but BA.5 had a number of additional mutations that affected non-S-protein fragments of the coronavirus genome. As a result, the BA.5 subvariant, in addition to easily bypassing the defense mechanisms of even an immune system prepared for invasion, is more aggressive and infectious than all the others. [5] [6]

This is why preventive measures involving the wearing of quality respirators with N95/KN95/KF94/FFP2/FFP3 level protection (rather than surgical masks), physical (social) distancing, air filtration and room ventilation (although WHO still resists unconditionally recognizing that the main route of transmission of COVID-19 infection is airborne [7]), and timely vaccination are extremely important before the BA.5 threat.

Existing vaccines adjusted to the original nonmutant SARS-CoV-2 coronavirus and not adapted to the specificity of any variant, if used in time as boosters, provide adequate protection against any variant of the virus for some time. Boosters that take into account mutational changes in the coronavirus improve the situation somewhat: The level of neutralizing antibodies increases on average by 1.5 times compared to the level provided by the “old” boosters, even if we are talking about a variant of coronavirus that is not included in the “new” booster. As a result, if a particular vaccine provided, for example, 86% protection against severe COVID-19, the “old” boosters can increase that rate to 98%, while the “new” boosters can increase that rate to 98.8%. [8] The difference in the rise in immune protection seems rather modest to take into account, but with a large population and a limited number of hospital beds, it matters a great deal.

On the other hand, there is an opinion that the expensive development and deployment of updated vaccine boosters that take into account the mutational characteristics of a particular coronavirus variant does not make much sense. Existing boosters are still quite good at preventing severe outcomes due to the formation of a pool of virus-specific B and T cells. But if the goal is to prevent infection in a mild-to-moderate form or to stop it from spreading, even the updated boosters won’t help much. [9] [10] [11]

First, high titers of neutralizing antibodies are required at all times, and these are dropping relatively quickly.

Second, the incubation period of COVID-19 infection is too short, so the immune system does not have time to recognize the virus and fight it off during those next few days when the infected person sheds enough virus to infect others with it. In contrast, the two-week incubation period for measles or rubella allows the immune system of the vaccinated person to develop enough antibodies to prevent transmission of the virus.

Third, there is the problem of so-called original antigenic sin (antigenic imprinting), when the ability to react to a new immunogen (in this case the antigen of a coronavirus variant in the updated booster) is reduced because the immune system has already “locked onto” the original immunogen (the antigen of a nonmutant coronavirus in existing vaccines and boosters), and therefore tends to use the existing immunological memory formed on the basis of the experienced viral attacks or previously received vaccines and the body’s reactions to them.

In the United States, the dominant anti-SARS-CoV-2 vaccines are those based on mRNA technology, incredibly innovative and never used on such a large scale before the COVID-19 pandemic. And now, with the emergence of clinically unproven bivalent boosters with the aim of Omicron, the U.S. continues to act as an experimental testing ground for this technology.

It should be recalled that seasonal flu vaccines are updated annually without the need for additional clinical trials. [12]

The degree of protection of the updated bivalent vaccines, Comirnaty and Spikevax, will become roughly clear when their clinical trials are completed, which, however, do not assess the effectiveness of the vaccines, but the level of neutralizing antibodies, otherwise the studies would be too costly.

Another question is whether the updated vaccine boosters will be in demand, because as of the end of August 2022, 67% of Americans were fully vaccinated, 49% had received the first booster, and 34% of those 50 and older had applied for a second booster. It is possible that people are so tired of the pandemic that they have lost interest in the “never-ending vaccination” race: Many mistakenly believe that protection from a previous vaccination or COVID-19 infection is enough.

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Julia Mardi

BioPharma Media’s Scientific Editor.

Julia strives to recognize in advance in which direction the pharmaceutical industry is moving. Her professional interests include gene therapy, immune checkpoint inhibitors, molecular biology, and drug repurposing.

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