What Are the Benefits of a Fourth Vaccination Against COVID?

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The fourth vaccination against COVID-19 is the subject of intense discussion. Immunity against new Omicron variants (currently BA.4 and BA.5) is getting weaker and weaker. Is another vaccination with the available vaccines worth it?

For Leif Erik Sander, MD, director of infectious diseases and pneumology at Charité University Medicine in Berlin, Germany, the latest data send a clear message. “The COVID-19 vaccination is still effective against Omicron. After three doses of the vaccine, it continues to prevent severe diseases, respiratory failures, and death,” he reported at the 62nd Congress of the German Pneumology and Respiratory Medicine Society in Leipzig.

The most recent data from the United Kingdom show that the vaccine’s effectiveness against Omicron decreases after just a few months, which speaks in favor of a fourth vaccination. “Omicron is a development that we did not anticipate occurring so early on,” said Sander.

In terms of phylogenetics, Omicron is far removed from the previous variants of concern. More than 30 mutations to the spike protein (the antigen that is vaccinated against) foster the loss of immunity.

Boosters Broaden Immunity

“The booster makes all the difference here,” emphasized Sander. Experiments at the Charité Berlin show that after double vaccination, the vaccination sera from healthy young people no longer neutralizes Omicron. But a third vaccination confers a very good neutralizing titer, even against Omicron.

“The third vaccination broadens the humoral immune response against the spike protein so that conserved epitopes that are unchanged, even in Omicron, are addressed, with the result that you have neutralization capacity again,” the infectious diseases specialist explained.

Continued Protection

However, data from the United Kingdom on vaccine effectiveness show where the limit lies. Initially, after three doses, vaccine effectiveness against symptomatic disease after Omicron infection is very good. This effectiveness decreases significantly over the course of the next few months. “Lots of people experience an Omicron infection despite the booster,” said Sander.

Nonetheless, the high incidence of Omicron infections in the recent past has not overwhelmed the healthcare system. “This is because the vaccine’s effectiveness against severe diseases that require hospitalization and against respiratory failure is still good in the at-risk population over the age of 65, once they have had their three vaccinations,” said Sander. The data also show that there is good protection of over 90%, even against mortality.

Waning Observed

It could be said that currently, vaccination even continues to work against Omicron, says Sander. It prevents severe disease, respiratory failure, and death. Nonetheless, after just 3 months, a slight waning of immune protection can be observed in all three endpoints.

Therefore, the question arises as to whether a fourth vaccination is worthwhile. In Israel, “Delta was successfully eradicated with the third vaccination,” and now they are trying this again for Omicron with a fourth vaccination, reported Sander.

Fourth Vaccination Protective

The first investigations show that protection against severe disease can be increased once more. “For the over-60s, protection is almost quadrupled through the fourth vaccination,” says Sander. “However, this is still plagued with a lot of uncertainty; it is still not known how stable it is.”

There is hope on the basis of results of an as yet non-peer-reviewed study from Sweden, which is currently available only as a preprint. That study shows that a fourth vaccination in a high-risk population of care-home residents and people older than 80 years can halve overall mortality. “If this can be confirmed and replicated, it must be recommended quite extensively for this high-risk group,” said Sander. The Standing Committee on Vaccination in Germany is currently recommending that high-risk groups be vaccinated against COVID-19 for the fourth time. To date, though, this has only been implemented halfheartedly.

Propensity for Mutation

Omicron keeps developing. Following BA.1 and the more infectious subvariant BA.2, BA.4 and BA.5 are spreading in Germany. “To date, there is no evidence that vaccine protection against severe diseases has changed as a result of BA.2 emerging,” said Sander.

However, the loss of immunity against BA.4 and BA.5 is more strongly pronounced. “If you were infected with BA.1, you are not immune to BA.5,” says Sander. Lessened immunity from BA.4 and BA.5 is even more pronounced. “Anyone who was infected with BA.1 is not immune to BA.5,” says Sander. The two clades not only have spike protein mutations shared by BA.2 but also additional spike protein mutations. According to the expert, it could well be that these strains will prevail because they are best able to avoid the immunity of the population.

Adapted Vaccines Feasible?

“Vaccines adapted to BA.1 were developed very early on and were also part of clinical research,” said Sander. The initial data indicate that additional antibody responses are being mobilized that may neutralize the new variants.

It was deduced from trials on monkeys that the available vaccines were so good that only small improvements were to be expected, said Sander.

Moderna’s Adapted Vaccine

The US pharmaceutical company Moderna recently submitted the first results regarding its bivalent Omicron vaccine mRNA-1273.214, which is adapted to Omicron BA.1. Data from BioNTech are expected soon.

Moderna tested a booster that contains both the spike mRNA from the original vaccine and a new mRNA adapted to the Omicron variant BA.1. The experimental vaccine mRNA-1273.214 exhibited an eightfold increase in geometric mean neutralization titer against Omicron in study participants who were seronegative at the start, compared with the already-approved vaccine.

In its latest notice, Moderna did not publish any data on how effective the updated vaccine is against the virus variants BA.4 or BA.5. Data on clinical endpoints, such as hospitalization or mortality, are also not available.

Conservative Epitopes

Should it be assumed that the development of vaccines will always lag the emergence of new subvariants? In this respect, Sander appears optimistic. “The immunological mechanism is clear, that various B cells and antibodies will be formed that are directed against conservative epitopes that have various variants. This is good news, since we do not want to protect against BA.1 now, just for BA.8 to emerge when the vaccine goes to market. We want to protect ourselves as broadly as possible, and it seems like it may be possible to do so with this vaccine.”

Double Vaccination?

Sander anticipates that a fourth vaccination against COVID-19 will occur with the next wave of the coronavirus in September or October. He remarked that coupling it with the influenza vaccination should be considered.

The coronavirus pandemic has led to shifts in other seasonal waves of pathogens. In the summer, pediatric departments were unexpectedly inundated with children suffering from RSV infections. And while the flu season over the past 2 years has been almost absent, the influenza wave may occur significantly earlier than usual this year.

“In Australia, the influenza wave arrived much earlier this year than usual, which may of course also be fruitful for us,” said Sander. “Perhaps we will also get influenza as early as in September or October. I would then plead for vaccine centers to be allowed to vaccinate against both influenza and COVID-19 at the same time. Maybe then we will also have a reasonable influenza vaccination rate,” he added.

This article was translated from the Medscape German edition.

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