Breakthrough Omicron infection may boost immunity against new variants

• Current vaccines protect most people against severe COVID-19 from all SARS-CoV-2 variants.
• Breakthrough infection from new variants is increasingly common in people who have been previously vaccinated or had the infection.
• Two new preprint studies suggest that breakthrough Omicron infection may give vaccinated people greater resistance against new Omicron variants.
• A peer-reviewed study has also found that the immunity from vaccination can be enhanced by an Omicron infection, but that Omicron infection alone gives little immunity to other variants.
• The researchers suggest that Omicron-based booster vaccines may increase resistance to new COVID-19 variants.

With little sign that the COVID-19 global pandemic will end any time soon, the hunt is on for effective ways to prevent repeated infections. The rapidly developed vaccines are very successful in preventing severe illness, hospitalization, and death, but new variants still cause breakthrough infections in many people.

Now, two preprint studies, which have not yet been peer-reviewed, have found evidence that a breakthrough Omicron infection can afford additional protection to those who are already vaccinated.

A third, peer-reviewed study, has confirmed this finding.

The first study, sponsored by BioNTech — which makes the Pfizer vaccine — found an increase in memory B cells and cross-variant neutralization after breakthrough infection.

The second, an international study led by scientists at the University of Washington, identified an ultrapotent antibody that appears to work against multiple Omicron variants, and detected neutralizing activity by antibodies in the lining of the nose following breakthrough infection.

Breakthrough infection boosts defence

The BioNTech study used a cohort of people who had been double or triple vaccinated. They were divided into four groups:

• Double vaccinated who had not experienced breakthrough infection after vaccination.
• Triple vaccinated with no breakthrough infection.
• Double vaccinated with breakthrough infection by SARS-CoV-2 Omicron.
• Triple vaccinated with breakthrough infection by SARS-CoV-2 Omicron.

The researchers tested blood samples taken from all participants and assessed the serum neutralizing capacity — the ability of antibodies to stop the virus from binding to receptors and replicating. They performed neutralization tests using both a pseudovirus (a version of the virus that cannot cause disease) and a live virus.

The pseudoviruses had the spike proteins of Omicron variants BA.1 or BA.2, or other SARS-CoV-2 variants of concern (Wuhan, Alpha, Beta, Delta).

In participants who had not had breakthrough Omicron infection, neutralizing antibody response was, as might be expected, stronger in those who had received 3 vaccines.

It was strongest against the earlier variants of concern, with a much-reduced effect against BA.1 and BA.2. Neutralization of these Omicron variants was virtually undetectable among double-vaccinated individuals who had not had breakthrough infection.

Researchers saw the highest levels of neutralizing antibody activity against BA.1 and BA.2 in sera from triple-vaccinated people with Omicron breakthrough infection.

All vaccinated individuals had memory B cells against SARS-CoV-2. However, those with breakthrough infections showed a much greater frequency of memory B cells against many variants of concern.

“The question we need to ask is: what would be the consequence of boosting with Omicron?”

— Prof. Jonathan Stoye, principal group leader at the Francis Crick Institute in London

Neutralizing activity in the nose

The second study compared plasma from individuals in the following 6 groups:

• Those who had an infection early in the pandemic who were then vaccinated with 2 doses.
• Those who had an infection early in the pandemic who were then vaccinated with 3 doses.
• Those who were vaccinated who then had a breakthrough infection of Delta.
• Those who were vaccinated with 2 doses who then had a breakthrough infection of Omicron.
• Those who were vaccinated with 3 doses who then had a breakthrough infection of Omicron.
• Those vaccinated with 3 doses with no prior or breakthrough SARS-CoV-2 infection.

They found good plasma neutralizing activity against Omicron BA.1 and BA.2 from both vaccination and breakthrough infections. However, breakthrough infections appeared to induce neutralizing activity in the nasal mucosa (the lining of the nasal cavity).

The researchers also identified an ‘ultrapotent pan-variant antibody’ which appeared unaffected by Omicron spike mutations.

Also, as in the previous study, infection with Omicron induced the recall of B cells that had been produced following vaccination.

The researchers suggest that the ultrapotent pan-variant antibody might be the focus of future clinical development. They also urge further research into nasally administered COVID-19 vaccines following their finding of neutralizing antibodies in the nose.

Limited boost from Omicron alone

A peer-reviewed study, just published in Nature, reported similar findings. This study found that while Omicron infection alone affords little cross-variant immunity, a breakthrough infection following vaccination does enhance immunity against multiple variants.

In both mice and humans, the researchers showed that Omicron infection enhanced pre-existing immunity from vaccination. Unvaccinated individuals with Omicron infection showed limited neutralization of only Omicron.

These findings concur with advice from GAVI — the vaccine alliance — that antibodies produced from previous Omicron infection in individuals who had been vaccinated against COVID-19 afforded greater protection against new variants than those from people who had recovered from natural infection alone.

Pointers for new vaccines

The researchers are not suggesting that people who are vaccinated should try to get an Omicron infection to increase their resistance to possible new variants, as the risk of long COVID is very real. However, the findings might suggest new directions for vaccine development.

Prof. William Schaffner, professor of medicine in the division of infectious diseases at the Vanderbilt University School of Medicine in Nashville, TN, told Medical News Today:

“There’s already been a fair amount of discussion in the U.S. that come the Fall, we will have COVID-19 vaccine 2.0, which may be what we call a bivalent vaccine. It has 2 kinds of protection — the traditional one that we already have, but they will add something that is much more Omicron specific.”

Prof. Stoye agreed:

“An important goal of current coronavirus vaccine research is to develop a vaccine capable of protecting against a wide range of coronaviruses, a so-called pan-specific vaccine. [These studies] would appear to represent an important step in this direction.”

Until these new vaccines are available, the advice is to take the existing vaccines and boosters when offered — they are still providing good protection against severe COVID-19.

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