Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused the 2019 Coronavirus Disease (COVID-19) pandemic and sparked a period of overwhelmed health services and economic instability as the virus made its way around the world.
The Omicron variant emerged in November 2021 and immediately raised serious concerns because of its unprecedented portability.
To learn: Booster of the mRNA-1273 vaccine reduces the escape of SARS-CoV-2 omicrons from neutralizing antibodies. Image source: hedgehog94 / Shutterstock
A new preprint on the medRxiv * server reports the results of a study focusing on its immune evasion traits, specifically its ability to be neutralized by antibodies against the previous SARS-CoV-2 variants or against that in COVID-19 vaccines used to escape spike antigen.
background
Several variants of the virus have emerged in the two years since the pandemic began. While some were lost sight shortly after they appeared, others have been observed to be more transmissible, more virulent, or more efficient at evading the host’s immune responses than the ancestral variant.
The ability to evade neutralization by natural and therapeutic antibodies means that a certain variant is referred to as a variant of concern (VOC), as does a significantly increased transferability regardless of environmental changes. The earliest variant to emerge was the D614G strain, which quickly replaced the ancestral Wuhan strain by May 2020 due to its increased ability that made rapid spread more likely.
During the D614G dominance, the Moderna mRNA 1273 vaccine was developed. Clinical studies, in particular the phase III study on coronavirus efficiency (COVE), showed an effectiveness of 94% in reducing the frequency of symptomatic illnesses after SARS-CoV-2.
The titer of binding and neutralizing antibodies against the D614G spike correlated well with the effectiveness of the vaccine in this study. Both results led to this spike protein being considered as a reference point for vaccine development and neutralization testing.
It is important to remember, however, that the D614G variant is among the most easily neutralizing variants of SARS-CoV-2 to date. It remained dominant until the beginning of 2021, when the alpha variant took over, only to be quickly replaced by the delta variant.
Both the alpha and delta variants showed the ability to withstand neutralization by antibodies elicited by the Moderna vaccine, but the neutralization capacity only decreased two to three fold compared to D614G. There were also other VOCs such as the beta variant that had been causing local outbreaks in South Africa for several months and showing marked resistance to vaccine-induced antibodies. Even so, the messenger ribonucleic acid (mRNA) vaccines like Moderna mRNA-1273 continue to offer significant protection against the variant, with only a minor decrease in effectiveness against serious illness and death.
Omicron was also first reported in South Africa in late 2021. It has the largest number of spike mutations to date of any variant with 15 mutations in the spike receptor binding domain (RBD), which is the target of over 50 neutralizing antibodies.
What did the study show?
The current study describes the results of neutralizing assays of the Omicron variant with serum samples from persons who had received full vaccination with mRNA-1273 (100 μg) in a pseudovirus assay. The assays of these samples were performed independently in two different laboratories.
Two sets of samples were used. The first contained selected samples with high neutralizing titers against D614G, while the second had moderate titers. Both Omicron and Beta Spike variants were tested to compare the two directly.
In a second series of tests, serum samples from vaccinated individuals who had received two doses of mRNA-1273 (100 µg) and a third booster of 50 µg were examined in the two laboratories, but different samples were sent to each laboratory. While one laboratory tested serum from people who received a 9 month booster, the other used serum samples from a clinical study in which people received a heterologous booster four or more months after the second dose, particularly those D614G infected with the highest response.
The researchers wanted to understand how much Omicron resisted neutralization by vaccine-induced antibodies compared to Beta or D614G. They found that the geometric mean titre (GMT) of the half-maximal infectious dose (ID50) in the two laboratories was reduced 84- and 49-fold when it came to neutralizing Omicron. Conversely, the beta VOC also had reduced ID50 GMT values, but only around 14 times and 9 times lower.
After the 50 μg boost was administered, the strength of neutralization increased 12-fold, with the ID50 being six and four times less effective than the D614G strain and ~ 3 times less than the Beta strain. In other words, the third dose booster improved neutralization for both the beta and omicron variants.
In an interesting subset of samples, vaccinated subjects were followed up for two weeks after the second dose, before the booster dose, and two weeks after the second dose. Two of the seven participants became infected with breakthrough infections about five to six months after the second dose, but before the booster dose.
During this time, the alpha and delta variants dominated in the USA. The antibodies induced by the vaccine were thus highest two weeks after vaccination against D614G, but lowest for Omicron. In this situation, the Omicron titers were reduced 35 times, but the beta was 9 times lower than the D614G.
The neutralizing titers fell sharply on the day of the booster, but were at their peak two weeks after the booster, in order to exceed the titers reached after the second dose in all three variants.
The ratio of the ID50-GMT values at this point in time was 13: 1 and 7: 1 for the Omicron and beta variants, respectively. Two subjects infected 5 months after the second dose had a higher response to the booster than the titers with the booster alone.
This increase in the neutralizing titer was observed in all three variants, although none of them had encountered the Omicron variant by then.
Infection with an earlier variant can increase the vaccine response to all three variants, and this additional vaccine boost can further increase that response. “
Conclusion
The results of this study show a 49- to 84-fold reduction in Omicron neutralization titers in fully vaccinated subjects (mRNA 1273 vaccine) compared to D614G. This indicates a higher risk of symptomatic illness after breakthrough infections. However, this can be mitigated by a booster dose of the same vaccine.
It should be noted that the study was small and the follow-up was brief. Further studies should investigate the results of this preliminary investigation into the antibody escape potential of Omicron after vaccination with mRNA-1273 and after a third booster dose.
*Important NOTE
medRxiv publishes preliminary scientific reports that are not peer-reviewed and should therefore not be considered conclusive, that guide clinical practice / health-related behavior or are treated as established information.
