The emergence of the B.1.1.1599 (Omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global concern. Mutations in the spike protein of the virus have altered its pathogenic potential. It is expected that these mutations have reduced the neutralizing antibody recognition in the virus and facilitated its spread.
There are numerous antibody targets in the SARS-CoV-2 spike protein, but polyclonal neutralizing responses are dominated by antibodies to the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the Spike. Aggregation of ~20 RBD and NTD mutations in a polymutant spike protein (PMS20) was required for evasion of polyclonal antibodies elicited in the majority of individuals who had been infected, or who had received two doses of an mRNA vaccine. Notably, several of the changes in the PMS20 spike are the same or similar to the changes in the emergent Omicron variant spike leading to the prediction that Omicron would exhibit substantial antigenic escape.
The aim of a new study published in medRxiv* preprint server was to determine the ability of individuals with varying exposure to SARS-CoV-2 infection and vaccination, to neutralize SARS- CoV-2 pseudotypes with spike proteins corresponding to the parental virus used in vaccine immunogens, PMS20, or the emergent Omicron variant.
Total 169 samples were collected longitudinally. Three types of samples were collected approximately one, five to six, and 12 months after initial vaccination or infection from three longitudinal cohorts:
- Convalescent individuals who did or did not receive two doses of the Pfizer/BNT or Moderna mRNA vaccine between six months and 12 months after infection.
- Uninfected individuals who received three doses of the Pfizer/BNT mRNA vaccine.
- Uninfected individuals who received the J&J Ad26 vaccine.
All samples were studied for the binding, neutralization titer, or donor demographic characteristics.
The Omicron spike coding sequence was derived from sequence ID EPI_ISL_6640919. A furin cleavage site mutation (R683G) was introduced that does not change the neutralization properties of the SARS-CoV-2 spike protein but enables higher titer pseudotyped viral stocks to be generated from transfected cells. Individual plasmid clones were completely sequenced, and a single correct clone was used.
Neutralizing titers were measured using a SARS-CoV-2 pseudotyped HIV-1-based assay that recapitulates neutralizing titers obtained with authentic SARS-CoV2. Plasmas were serially diluted and then incubated with a SARS-CoV-2 spike (Wuhan-hu-1, PMS20 or Omicron). The NT50 for each plasma was measured twice in two independent experiments with two technical replicates each.
The results revealed that similar to PMS20, the Omicron variant pseudotyped virus was substantially resistant to neutralization by plasma compared toWuhan-hu-1. Unvaccinated individuals who acquired the infection exhibited markedly reduced plasma neutralizing activity—including many with sub-detectable titers against Omicron pseudotypes. Additionally, plasmas of plasmas from vaccinated individuals elicited notably impaired ability to neutralize the Omicron variant. In particular, J&J vaccine recipients were poor at neutralizing the variants.
Meanwhile, it is known that vaccinating previously infected individuals can considerably increase the neutralizing titers and spectrum. The present study depicted that vaccination of convalescent individuals or boosting of an initial vaccine response through a third mRNA (Pfizer/BNT) vaccine dose, more than six months after the administration of the first two doses, resulted in substantial neutralizing activity against PMS20 and against Omicron.
For individuals who received two doses of an mRNA vaccine approximately six months prior, followed by a third, booster mRNA vaccine dose about one month before sampling, the median and range of the NT50 values represented a comparative deficit in potency by 55±45 fold for PMS20 and 18±14 fold for Omicron, with the Wuhan-hu-1 pseudotype.
It was inferred that boosting immunity with mRNA vaccines can aid in elevating neutralizing titer and span in individuals who had earlier acquired a SARS-CoV-2 infection or who were vaccinated with Wuhan-hu-1-based mRNA vaccines. Neutralizing titers against the Omicron variant were specifically surplus in all infected individuals who received the third mRNA vaccination dose. Whereas, the neutralizing titers were low or undetectable in many unvaccinated individuals with a history of infection or those who were given two doses of mRNA vaccine.
The degree of neutralizing antibody escape by the Omicron variant is high compared to the naturally occurring SARS-CoV-2 variants. Antibody waning post-infection or vaccination has also contributed to low span and the reduced levels and span of neutralizing antibodies among the previously infected and in those who received two mRNA vaccine doses or the Ad26 vaccine.
Incidentally, people who received three doses of mRNA vaccines and those who had SARS-CoV-2 before mRNA vaccinations showed elevated neutralizing antibody titers against Omicron. It was stated that future studies must target the development of broad-spectrum vaccination strategies which could prevent severe disease from most mutants of the deadly virus and may also complement the existing vaccines.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.