Vaccines for New COVID Variants Might Come Too Late

Michael van den Heuvel

June 30, 2022

Not surprisingly for an RNA virus, SARS-CoV-2 is proving its propensity for mutation. In swabs from infected patients, the proportion of the Omicron subvariant BA.4 is 2.1% (calendar week 21) compared with 1.2% in the previous week. In the same period of time, the frequency of subvariant BA.5 jumped up to 10.0%compared with 5.0% in the previous week.

This dynamic leads to a crucial question: What can physicians expect from modified vaccines, given the long waiting time? The most recent example is the announcement from Moderna that it will soon be applying for approval for a bivalent vaccine against wild type and against Omicron.

Moderna's Data

Moderna is only giving a rough overview of the data on the new vaccine mRNA-1273.214. It contains the approved molecule mRNA-1273 (Spikevax) and a vaccine candidate that targets Omicron. It should be noted that the vaccine targets the Omicron subvariant BA.1.

The mRNA-1273.214 vaccine achieved all primary endpoints in the phase 2/3 study. Two concepts are important for vaccine research. The antibody titer is specified as a geometric mean titer (GMT). Compared with a mathematical mean, this value is more robust in the face of strong fluctuations. The effectiveness of neutralizing antibodies is designated as a geometric mean response (GMR), which, depending on dilution, is able to deactivate a certain percentage of all viruses.

  • The GMR was 1.75 (97.5% CI, 1.49-2.04).

  • A booster dose of mRNA-1273.214 increased the GMT against Omicron roughly eightfold compared with baseline values.

  • The primary endpoint of noninferiority compared with the originally circulating SARS-CoV-2 was also achieved, with a GMR of 1.22 (1.08-1.37).

  • For seronegative individuals 1 month after administration, the GMT against wild type for mRNA-1273.214 was 5.977 (5.322-6.713) compared with a GMT for mRNA-1273 of 5.649 (5.057-6.311).

  • The GMT against Omicron for mRNA-1273.214 was 2.372 (2.071-2.718) compared with a GMT for mRNA-1273 of 1.473 (1.271-1.708).

  • The titer-binding antibody titer was also significantly higher against all other potential variants (Alpha, Beta, Gamma, Delta, Omicron) with mRNA-1273.214 compared with mRNA-1273.

The booster vaccination with mRNA-1273.214 was well tolerated by the 437 study participants. The safety and reactogenicity profile was similar in mRNA-1273 as it was for the booster.

Open Questions

"The data from Moderna show that people who received the fourth vaccination with the bivalent vaccine have more neutralizing antibodies against Omicron in their blood than did people who received the fourth vaccination with a conventional vaccine," said Carsten Watzl, PhD, general secretary of the German Society of Immunology. "These data demonstrate that protection against Omicron is also better with the bivalent vaccine," he said. However, the data cannot be used to deduce how effective it may be against infections or severe diseases.

"People still have more neutralizing antibodies against the original virus than against Omicron after the fourth vaccine," said Watzl. Still, protection against infection with Omicron was improved. "It is still not as good as the protection against infection with the earlier variants."

Does it make sense to develop a vaccine against BA.1, while BA.4 and BA.5 dominate current events? The new vaccine is targeted against BA.1. By fall, this Omicron variant will have disappeared into insignificance.

"Of course, the virus is once again faster than the vaccine development," said Watzl. "But the difference between BA.1 and BA.5 is much smaller than the difference between the original vaccine and BA.5." Therefore, a vaccine adapted to BA.1 still makes a lot of sense. It will just stimulate the immune cells, which can recognize the original variants as well as Omicron. Watzl hopes that the immunity will be variant-independent and may also offer protection against future variants.

Who Would Benefit?

"A booster in the fall with the adapted vaccine would be worthwhile for those who would actually respond to a booster, ie, those that do not have such a high level of antibodies," according to the assessment by Andreas Radbruch, MD, scientific director of the German Rheumatism Research Center Berlin (DRFZ). "It is predicted that a booster would increase the respiratory tract's relatively short-term protection against infection again, ie, protection against infection for the months of the next wave." Radbruch speculates that protection against infection would possibly be better because new variants would also be covered.

"For people under 60 with a healthy immune system, I do not currently see any reason for a fourth vaccination," said Watzl. This group still has "very good protection against severe disease," but they will experience a breakthrough infection sooner or later and develop a hybrid immunity.

"However, people with a weak immune system and the elderly still have a relatively high risk of severe disease," said Watzl. They should increase their immunity in the fall with an adapted vaccine.

Seasonal Coronavirus Vaccination?

The method of regularly updating antigens or their gene sequence in vaccines is reminiscent of the seasonal vaccine against influenza; every year, vulnerable patients receive a new vaccination.

"People with a healthy immune system under 60 probably update their immunity with an infection every few years," according to Watzl's assessment. "If you do not want to have any contact with the virus at all, you can be vaccinated every year in the fall and observe additional hygiene measures, et cetera, in the event of high incidence." However, for people with weak immune systems and people older than 60 years, an annual immunity refresher is worthwhile.

This article was translated from the Medscape German edition.

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