Highlights

Moderna has introduced Spikevax bivalent Original / Omicron (mRNA-1273.214), the world’s first vaccine to protect against the Omicron variant of the SARS-CoV-2 coronavirus.

mRNA-1273.214, which is officially called Spikevax bivalent Original / Omicron, is a bivalent vaccine that combines mRNA sequences encoding S proteins of the original nonmutant SARS-CoV-2 coronavirus and its Omicron strain (B.1.1.529 [BA.1]). These single-stranded mRNA sequences are named elasomeran and imelasomeran, respectively.

Spikevax bivalent Original / Omicron is a further development of the original Spikevax (elasomeran; mRNA-1273) vaccine.

The United Kingdom became the first country in the world to approve the use of Spikevax bivalent Original / Omicron. The conditional decision was made by the Medicines and Healthcare products Regulatory Agency (MHRA).

Spikevax bivalent Original / Omicron vaccine is authorized for use as a booster for the active immunization of fully vaccinated adults who have received a complete course of primary vaccination to prevent COVID-19 infection caused by the SARS-CoV-2 coronavirus.

The U.S. is about to approve a slightly different bivalent Moderna booster, mRNA-1273.222, which targets protection specifically against BA.4/BA.5 subvariants of Omicron and which is still under clinical review.

Pfizer and BioNTech have prepared an updated bivalent version of mRNA vaccine Comirnaty (tozinameran; BNT162b2) that takes into account the mutational features of BA.4/BA.5 subvariants. The necessary data has been sent to the U.S. Food and Drug Administration (FDA).

 

Protective Effectiveness of Spikevax Bivalent Original / Omicron

Regulatory approval of Moderna mRNA-1273.214 vaccine was based on the results of the clinical trial NCT04927065 phase 2/3 (nonrandomized, open-label, multicenter) in which SARS-CoV-2 uninfected adult volunteers (n=812) received a second booster dose of vaccine (actually the fourth dose after two doses of the primary vaccination followed by the first booster dose, all with Moderna vaccine): either the original Spikevax vaccine (mRNA-1273) or the experimental bivalent mRNA-1273. 214 vaccine.

It was found that in the entire subject population (regardless of the presence or absence of prior history of COVID-19 coronavirus infection) at 28 days after vaccination, mRNA-1273.214 compared with mRNA-1273 elicited an equally effective neutralizing antibody response against the original (nonmutant) SARS-CoV-2, with a higher geometric mean titer (GMT) of 6619 (95% CI: 5942–7374) — versus 6048 (95% CI: 5466–6691). Compared with the GMT before booster administration, it increased 4.1-fold (95% CI: 3.8–4.4) — versus an increase of 3.1-fold (95% CI: 2.9–3.4).

Among those who had never had COVID-19 before and those who had had COVID-19 before, the neutralizing antibody GMT increased 4.7- and 2.6-fold in the mRNA-1273.214 group — versus a 3.7- and 1.9-fold increase in the mRNA-1273 group.

In the entire population, the neutralizing antibody GMT against the Omicron variant (B.1.1.529) went to 3070 (95% CI: 2685–3511) — vs. 1933 (95% CI: 1681–2222). When adjusted for the pre-booster GMT, it rose 7.1-fold (95% CI: 6.5–7.8) — vs. a 3.8-fold increase (95% CI: 3.4–4.2)

Among those without and with a history of COVID-19, the indicated GMT increased 8.0- and 4.8-fold in the mRNA-1273.214 group — vs. an increase of 4.4- and 2.5-fold in the mRNA-1273 group.

In the entire population, the neutralizing antibody GMT against Omicron subvariants BA.4 and BA.5 provided by mRNA-1273.214 was 941 (95% CI: 826–1071), a 5.4-fold (95% CI: 5.0–5.9) increase in GMT of 173 (95% CI: 147–202) before this booster was administered.

In the subgroup of participants without prior SARS-CoV-2 infection, this GMT increased 6.3-fold; in the COVID-19 subgroup, it increased 3.2-fold.

The mRNA-1273.214 booster compared with mRNA-1273 booster increased binding antibody GMTs against the original SARS-CoV-2 and its Alpha, Beta, Gamma, Вelta, and Omicron variants (regardless of the presence or absence of coronavirus infection in a history) by 1.14 (95% CI: 1.07-1.21), 1.17 (95% CI: 1.09-1.24), 1.14 (95% CI: 1.07-1.22), 1.16 (95% CI: 1.09-1.24), 1.10 (95% CI: 1.03-1.16), and 1.23-fold (95% CI: 1.15-1.32), respectively.

 

Expert Comments

The highly mutational nature of the SARS-CoV-2 coronavirus makes new generations of the virus less susceptible to vaccines and drugs. To successfully combat the COVID-19 pandemic, the pharmaceutical armamentarium must be updated to account for SARS-CoV-2 mutations.

In late November 2021, the Omicron variant (B.1.1.529) of the SARS-CoV-2 coronavirus emerged, subsequently splitting into five distinct sublineages: BA.1, BA.2, BA.3, BA.4, and BA.5. Omicron, which spread rapidly across the globe, has an improved ability to evade immune response, both post-COVID-19 and vaccine-induced. The aggressiveness and contagiousness of Omicron has led to a new wave of COVID-19 infections.

Most circulating Omicron variants now belong to sublineage BA.2. However, the prevalence of BA.2.12.1 (subvariant of BA.2), BA.4, and BA.5 is increasing rapidly in all parts of the world. In the United States, for example, as of mid-August 2022, infection with BA.5 was responsible for 89% of all new cases of COVID-19.

Of particular concern is sublineage BA.5, the worst version of the coronavirus humanity has ever encountered. BA.5, with its enhanced ability to evade immune system surveillance, easily circumvents all existing vaccines, drastically reducing their protective effectiveness. The contagiousness of BA.5 is far superior to that of the original Omicron, which will lead to a new wave of COVID-19, in turn resulting in more hospitalizations and deaths. However, the current situation is more or less under control: Since the vast majority of the world’s population has been exposed to Omicron, they have developed a certain cross-immunity which partially protects against BA.5.

It should be understood that even with the current set of vaccines, which are in no way adjusted for Omicron, a full course of vaccination followed by a booster dose (or two) would in any case seriously reduce the risk of hospitalization and death. The incidence of breakthrough infections will definitely increase, but vaccine protection, even if it has lost its former near-absoluteness, will no doubt continue to hold back COVID-19 from progressing to a severe form.

Of course, it would be possible to think of face masks, social distancing, isolation and other measures universally introduced when the world was first confronted with the COVID-19 pandemic. However, people, societies and entire nations are simply tired of the burden of the coronavirus, so such prevention initiatives are not to be expected. This is why the emergence of vaccines updated and adapted to the mutational specificity of SARS-CoV-2, especially the Omicron variant, is more urgent than ever.

Moderna’s proposed Spikevax Bivalent Original / Omicron vaccine, administered as a second booster after an immunization course of two doses of original Spikevax vaccine followed by a booster, has the potential to provide adequate protection against Omicron variants of BA.4 and BA.5. Speaking of the category of people who have been vaccinated in a timely manner (and therefore have never had COVID-19) and who want to be well protected against infection in the future, the degree of protection provided by Spikevax Bivalent Original / Omicron has weakened considerably.

Thus, after the mRNA-1273.214 booster, the titer of neutralizing antibodies against BA.4 and BA.5 was 8.2-fold lower when compared with their titer against the nonmutant coronavirus. Nevertheless, these antibody levels were comparable with those achieved after third-dose Spikevax vaccination in the context of antibody production against Delta (B.1.617.2) and Omicron (B.1.1.529) variants: 727, 828, and 629, respectively. It remains to be seen how long such protection will last, because after 6 months after three doses of Spikevax the indicated antibody titers against Delta and Omicron decreased by a factor of 2.1 and 4.3, although they remained 8.4- and 3.8-fold above the pre-booster titers.

Moderna is not abandoning the battle against Omicron: mRNA-1273.222 booster under development is aimed at combating BA.4 and BA.5 variants. mRNA-1273.222 vaccine will enter civilian circulation in the fall of 2022. Apparently, the U.S. will approve this particular booster rather than mRNA-1273.214.

Considering that SARS-CoV-2 continues to mutate, a process that could last indefinitely, we should explore the possibility of developing a universal vaccine that would protect against all variants of SARS-CoV-2 as well as other coronaviruses once and for all. Relentless production of updated vaccines against SARS-CoV-2 is far from a solution, as the situation will take a turn similar to the ongoing fight against seasonal flu. New flu vaccines appear every year, but their effectiveness is decidedly insufficient (the vaccines have not kept up with the mutations) to conclusively defeat influenza.

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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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