The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, has led to over 103 million infections over 2.2 million deaths worldwide. With no targeted, effective antivirals and safe antivirals yet identified, the focus has largely been on non-pharmaceutical interventions (NPIs). These have included scrupulous attention to handwashing, wearing masks in public, social distancing and lockdowns at various (regional or national) levels.
Moreover, the rise of new strains of SARS-CoV-2 that have exhibited heightened transmissibility has led to questions about the neutralizing efficacy of the approved vaccines currently being administered in many parts of the world. Against this backdrop, a U.S.-based team of researchers at the University of Texas Medical Branch and Pfizer studied the Pfizer-BioNTech vaccine candidate - currently being rolled out in many parts of the world to high-risk individuals - to see if it still holds up against mutant strains of the virus. In doing so, the team yielded encouraging results.
.jpg "Study: Neutralization of spike 69/70 deletion, E484K, and N501Y SARS-CoV-2 by BNT162b2 vaccine-elicited sera. Image Credit: LookerStudio / Shutterstock")
Importance of vaccines against COVID-19
The only hope for the long-term control of this pandemic appears to be through the deployment of vaccines on a global scale. Consequently, immense scientific effort has been expended on developing safe and efficacious COVID-19 vaccines. These have been based on a variety of platforms, including DNA and RNA, live attenuated virus, inactivated virus, and viral proteins.
While some vaccines such as the Pfizer-BioNTech, Moderna and Oxford-Astra-Zeneca vaccines have recently become available, with millions having received one or more doses in different countries, many more are in the later stages of clinical development. Among them is BNT162b2 (i.e., the Pfizer-BioNTech vaccine), an RNA-based vaccine that has undergone nucleoside modification.
This RNA vaccine model includes the viral genetic material encoding for the full-length viral spike protein in its stabilized prefusion form.
Earlier findings
The BNT162b2 model has been observed to induce neutralizing antibodies to the virus in a dose-dependent manner. The geometric mean titers (GMTs) were either the same as or higher than those measured in an array of human serum samples from convalescent COVID-19 patients.
The same researchers conducted a placebo-controlled trial of the BNT162b2 vaccine, including about 44,000 participants aged 16 years or more. Two doses of the vaccine were administered. The vaccine was found to have an efficacy of 95% or more against the disease.
However, in the current study by the same team of scientists, the focus is whether the BNT162b2 vaccine is efficacious in preventing disease caused by newly emerging and rapidly spreading SARS-CoV-2 variants, including the UK, South Africa, and other regions of the world.
The reason for such questions is that the new variants have multiple mutations in their spike proteins, which are the targets of the majority of known neutralizing antibodies. Thus, the researchers aimed to test the effect of the most important spike mutations on the neutralizing antibodies elicited by this vaccine.
Study details
The researchers first generated three spike mutant viruses based on the clinical strain USA-WA1/2020. The first contains the spike N501Y mutation found on both the UK and the South African variants. The mutation affects the viral receptor-binding domain (RBD).
The mutant form of the spike not only enhances the binding of the virus to the host cell receptor angiotensin-converting enzyme 2 (ACE2), making the variant more infectious, but it allows the virus to infect mice as well.
The second mutant contains a set of mutations, deletion 69/70, N501Y, and D614G. Of these, the first is on the N-terminal domain of the S1 subunit of the spike, and has been suggested to cause an allosteric change in the conformation of the S1 subunit. The D614G mutation is present in the vast majority of circulating strains the world over.
The third mutant contains the E484K mutation, in addition to the N501Y and D614G mutations. The E484K mutation is also found on the RBD, and confers resistance on the containing variant to many monoclonal antibodies.
When compared with the wildtype USA-WA1/2020 strain, the researchers observed that all three produced similar-appearing plaques in cell culture. They tested sera from 20 participants who had received two doses of the vaccine, at an interval of 21 days. The sera were taken either 2 or 4 weeks after the second dose.
Each serum sample was tested for its ability to neutralize the wildtype strain and the three mutant strains, using the 50% plaque reduction neutralization assay (PRNT50). The neutralization titers were highly comparable for all sera, whether for the mutant or wild-type viruses, with less than a four-fold difference between the highest and lowest neutralization titer.
Results and implications
Of the 20 sera, ten had twofold neutralizing titers against the Δ69/70+N501Y+D614G virus relative to the wildtype virus, but six showed neutralizing activity against the E484K+N501Y+D614G virus but with only half the titers shown against the wildtype virus.
The neutralization GMTs of serum against the N501Y was ~1.5 times the GMTs against the wildtype virus, while the Δ69/70+N501Y+D614G and E484K+N501Y+D614G viruses had GMTs of neutralizing antibodies that were 1.4 and 0.8 the GMTs against the wildtype virus, respectively. These differences are too small to indicate any change in vaccine efficacy.
With influenza vaccines, a fourfold difference in the titer of hemagglutinin-inhibition antibodies indicates a significant change in influenza strain. Using the same criteria, it appears that these mutations do not affect the ability of antibodies induced by two BNT162b2 doses to neutralize the mutants studied here, compared to the parental strain.
The viruses used in this study do not contain all the mutations in the UK or South African variants, but this may not impact the results of the neutralization assays. Secondly, the study does not include data on the correlates of antibody-mediated protection against COVID-19.
For this reason, the neutralization titers are used to predict vaccine efficacy. These predictions are based on assumptions about the titers of neutralizing antibodies required for effective neutralization and how antibodies contribute to vaccine-induced protection against COVID-19 compared to cell-mediated immunity.
As a result, clinical data is essential to arrive at a solid understanding of how effective the vaccine is against these new variants. Meanwhile, monitoring of the worldwide infection scenario should go on uninterruptedly to avoid missing a dangerous strain, and to introduce necessary changes in the available vaccines. Such changes in the current mRNA vaccine are easy, due to the flexible platform used.
*Important Notice
bioRxiv 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.
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2021-02-02 19:05:00Z
CBMidWh0dHBzOi8vd3d3Lm5ld3MtbWVkaWNhbC5uZXQvbmV3cy8yMDIxMDIwMi9QZml6ZXItQmlvTlRlY2gtdmFjY2luZS1zaG93cy1wcm9taXNlLWFnYWluc3QtbmV3LVNBUlMtQ29WLTItdmFyaWFudHMuYXNweNIBeWh0dHBzOi8vd3d3Lm5ld3MtbWVkaWNhbC5uZXQvYW1wL25ld3MvMjAyMTAyMDIvUGZpemVyLUJpb05UZWNoLXZhY2NpbmUtc2hvd3MtcHJvbWlzZS1hZ2FpbnN0LW5ldy1TQVJTLUNvVi0yLXZhcmlhbnRzLmFzcHg
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