COVID boosters hamper SARS-CoV-2 Omicron

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused world-leading morbidity, mortality and social and economic disruption. Despite the deployment of vaccines, the emergence of new variants of immune evasion is a formidable obstacle to the end of the pandemic.

The most recent variant of this type is the Omicron variant (B.1.1.529). First reported on November 24, 2021, it has shown a tremendous ability to spread extensively and rapidly, beyond all previous variants, while resisting neutralization by antibodies caused by the vaccine. or by natural infection with previous variants, including the Delta variant.

It has become dominant in many countries and threatens to cause the next wave of infection. A new pre-printed research document reports on the current state of knowledge on the immune evasion capacity of this variant, linking it to the type of vaccine used and to the vaccination protocol.

The research is based on the numerous reports produced by several groups using the sets of vaccinated and convalescent sera available. These include sera from individuals infected with wild type, Alpha, Beta and Delta variants, using several neutralization assays and cell types.

Posted on bioRxiv * preprint site, the research aggregates data from 23 laboratories until December 22, 2021, to understand Omicron’s propensity to escape neutralization by antibodies.

Study: Analysis of Omicron SARS-CoV-2 neutralization data up to 2021-12-22. Image Credit: Viacheslav Lopatin /

What did the study show?

In the first group, nicknamed “2x-Vax”, all 44 individuals were fully vaccinated, regardless of the type of vaccine. This group shows the most significant uncertainty on the degree of escape of antibodies against Omicron compared to the wild type. So the headline drops about 19 times, on average, but this is likely to be significantly less than the actual drop.

The reason is that many of Omicron’s neutralization titers were below the limit of detection (LOD) of the assay, and sometimes the low titers against the reference antigen were to blame for the fold drops

The Omicron fold decreases compared to the wild type. Arrows indicate uncertainties in the point estimate due to titers below the limit of detection (LOD) of the assay. A short arrow marks readings with less than half of the Omicron titers below the limit of detection (LOD) of the assay, or conversely, the reference antigen titers are equal to or greater than the LOD. Long arrows indicate readings with more than about 80% of Omicron titers below the LOD. Light blue dots show NIH SAVE Laboratories, gray dots mark data points for which the reference antigen was not stated in the manuscript and is here assumed to be Wu-1. The continuous vertical line does not mark any change in folds.

In the group of “2x Vax + Inf” individuals who were fully vaccinated and who subsequently presented with flare-up infections, a similar pattern was observed. The largest decrease from the wild-type variant was 25-fold, but these were from individuals who had Delta infection and were sampled three days after hospitalization.

Among the convalescent group, the 20-fold average drop in Omicron titers relative to wild-type virus was the second largest drop. However, this was mainly due to a sharp reduction in sera from individuals sampled just three days after hospitalization with a wild-type variant.

Among the “Inf + 2 x Vax” cohort, comprising individuals who were fully vaccinated after becoming infected, the extent of fold decline for Omicron most closely resembled that of the triple vaccinated cohort. Most of the Omicron neutralizing titers were above the LOD, the average being a 12-fold decrease.

The triple vaccination group, which had received an additional booster dose, almost all had detectable Omicron neutralization titers, with lesser declines, at a 7-fold reduction compared to the wild type. They also showed a narrower range of distributions compared to those who had only completed the primary series of vaccinations.

Most of the samples were taken within one month of the additional dose, which requires longer follow-up to determine the course of these titres over time. The highest degree of certainty was with the use of messenger ribonucleic acid (mRNA) vaccines and with those infected prior to the double vaccination with these vaccines.

Interestingly, the fall factor with Omicron versus wild type does not correlate with the absolute magnitude of neutralizing titers against the wild type, indicating that there is a real improvement in immunity following administration of an additional dose of the vaccine.

The highest neutralizing titers for Omicron and wild type were reported in the Infected + vaccinated group, although the former was less than a tenth of the latter (460 and 5600, respectively). In the triple vaccinated group, titers were, on average, 40% and 70% of those in the above cohort (Omicron and wild type = 2200 and 330, respectively). In both cohorts, most of Omicron’s neutralizing titers were greater than the LOD, indicating that these values ​​are correct.

Along with the other groups, the large number of Omicron titers below the assay LOD increases the degree of uncertainty in the estimates and mean titers, indicating that the reported mean Omicron titer is likely a substantial overestimate. In comparison, the wild type titers were easily detectable and were> 1,500.

The mean Omicron titer in these groups ranged from 26 to 57, while the wild type titer ranged from ~ 500 to 1500.

The double vaccinated cohort showed lower titers with single dose J&J, or double Sputnik V, compared to two doses of AstraZeneca vaccine, and much lower than mRNA vaccine sera.

Pseudovirus neutralization titers were used as an indicator of protection against symptomatic disease. This showed that the Inf + 2x Vax group had greater than 80% protection, with two doses of AstraZeneca or Moderna vaccines. Omicron titles, while lower, would still provide 70% protection.

In the triple vaccine group, either vaccine would give> 80% protection against both variants within one month of the third dose. There would be 70% protection against symptomatic illnesses related to Omicron with all vaccines except CoronaVac, even with three doses. Protection estimates have not been made in other groups due to the large uncertainties involved and the efficacy of the vaccine against Omicron not yet established.

Pseudovirus tests had wild-type titers relative to Omicron which were twice as high as with live virus tests in the 2x Vax cohort and three times higher in the triple vaccinated group.

What are the implications?

The data provided here led scientists to conclude that a double vaccination or a history of infection resulted in a 19-fold reduction in titers against Omicron. The extra vaccine dose, or infection breakthrough after two doses, led to a much smaller 7-fold reduction.

The question of how long this will persist is unanswered since all samples from the triple vaccinated group were taken one month after the last dose.

Again, “the significantly smaller drop and somewhat higher titers after a third vaccination is strong early evidence of the utility of the booster vaccination for increasing viral neutralization titers against Omicron, and therefore potentially for increasing vaccine efficacy. “

Second, the difference in the reported neutralization titers depending on whether pseudovirus or live virus assays were used should be investigated, as it could be due to the use of different types of sera with different assays. For example, most of the pseudovirus tests were performed using sera from individuals who had received the mRNA vaccines, but live virus testing with post-vaccination sera from J&J, Sputnik V and CoronaVac.

The latter are known to induce neutralizing titers lower than those of mRNA vaccines. However, vaccine efficacy is lower at higher titers with AstraZeneca with live virus testing compared to pseudovirus testing.

Nonetheless, in Feng et al.27’s study of vaccine efficacy (VE) against symptomatic 221 disease after two doses of AstraZeneca, they reported lower EV at higher titers in neutralization assays. live virus 222 versus pseudovirus neutralization.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.

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