New Astra-Zeneca B.1.351 vaccine AZD2816 strongly immunogenic against multiple SARS-CoV-2 variants of concern

In many countries, the rapid pace of vaccination against coronavirus disease 2019 (COVID-19) has helped to reduce the number of new cases and hospitalizations remarkably. Simultaneously, however, new strains are emerging that show resistance to antibodies elicited by earlier strains, and/or increased transmissibility.

A new study, released on the bioRxiv* preprint server, supports the efficacy of the wildtype ChAdOx1 nCoV-19 (AZD1222) vaccine against B.1.351, B.1.617.1 and B.1.617.2, while showing that a booster dose of vaccine based on the B.1.351 spike induces further increase in antibody titers.

Background

These variants are called variants of concern (VOCs), the best-known being B.1.1.7 (Alpha), first identified in the UK; B.1.351 (Beta), in South Africa; and P.1 (Gamma), in Brazil, besides the most recently reported variants, B.1.617.1 (Kappa) and B.1.617.2 (Delta).

All VOCs identified so far contain the D614G mutation that increases infectivity, possibly by increasing the expression of the spike protein on the surface of the viral particle.

The L452R mutation is present in B.1.429 (Epsilon), B.1.617.1 and B.1.617.2, reducing susceptibility to neutralizing antibodies. E484K in both B.1.351 and P.1 isolates may increase spike-receptor binding as well as conferring antibody escape capability. Meanwhile, the N501Y mutation found in B.1.351, B.1.1.7 and P.1 variants impair neutralization when it occurs in combination with E484K and D614G.

Since the spike antigen, which is immunodominant as well as mediating viral entry, is the prime target of most neutralizing antibodies, especially the receptor-binding domain (RBD) of the spike, the accumulation of RBD and spike mutations may inevitably allow the VOCs to escape neutralization by antibodies induced by wildtype SARS-CoV-2.  

B.1.351 variant

B.1.351 is thought to have been responsible for the second wave of infection in South Africa, with proportionally more young patients than in the first wave. This variant contains N501Y and 484K, among other mutations in the spike protein, of which three are thought to enhance spike-receptor binding affinity.

The B.1.351 variant was first reported in October 2021, with three RBD mutations that increase spike-RBD binding and thus impaired neutralizing capacity.

Adenovirus-vectored and mRNA-based vaccines are easily tailored to incorporate mutated spike antigens to meet the challenges posed by newer variants. One such is the second-generation Astra-Zeneca vaccine, AZD2816.

Single-dose of AZD2816 produces cross-reactive immunity

In the current experiment, the researchers found that a single dose of either the new  vaccine or the original ChAdOx1 nCoV-19 (AZD1222) vaccine produced a robust antibody response. The same was the case when the booster was a mix of both vaccines.

The onset of antibody production was rapid, with little difference between day 9 and day 16 titers, indicating the potent immunogenicity of both vaccines.

Pseudovirus neutralization tests showed that both the wildtype variant and B.1.351 variant were successfully inhibited. Thus, cross-reactive immunity was elicited by one dose of the new vaccine.

One dose of AZD2816 also generated T cells reactive to both the spike variant in the original vaccine, that in the new vaccine, and that present in B.1.351. Interestingly, stimulation by pooled spike peptides revealed maximum response to the S1 domain of the spike, especially peptide antigens conserved in all three, with little response to the variant regions.

AZD2816 booster enhances cross-reactive antibodies

A booster dose of variant vaccine AZD2816 in mice that had received one dose of the original AZD1222 vaccine led to an increase in antibodies targeting wildtype and B.1.351 spike. Unexpectedly, antibodies to other variants, including P.1, B.1.429, B.1.617.1 or B.1.617.2, were also increased, in contrast to the antibody response induced by a single dose of the original vaccine.

Third dose of AZD2816 improves breadth of cross-reactive cellular immunity

When AZD2816 was given as a third booster dose to mice that had received two doses of AZD1222 4 weeks apart, the T cell response remained unchanged in magnitude and profile.

That is, the proportion of T effector, T effector memory, or T central memory CD4+
T cells were maintained intact after the third dose. The virus-specific response was mediated mainly by CD8+ T cells producing IFNγ and TNFα, both in third-dose and control cohorts. T effector and T effector memory CD8+ T cells were prominent in this cell response.

The third dose did enhance the number of variants recognized by the T cells. Here again, the cells were stimulated mainly by common spike peptides rather than variant regions.

In a typical two-dose AZD1222 regimen, the booster dose induced higher antibody titers against the wildtype spike after two doses, but not against B.1.351. Conversely, a third dose of AZD2816 after two doses of AZD1222 led to higher responses all around, especially against spike variants B.1.1.7 and B.1.429.

The sera from these mice neutralized multiple variants, including the wildtype virus, Beta, Kappa and Epsilon variants. A single booster with the new vaccine thus improves antibody responses to B.1.351 further while also inducing cross-reactive responses against other variants of the virus.

It is noteworthy that no adverse effects were observed with this booster dose.

What are the implications?

The use of a single dose of either wildtype or AZD2816 vaccine is shown to induce an efficient antibody and cellular immune response that binds and neutralizes both wildtype and beta variants of the virus.

Real-world data from monitoring shows that the earlier regimen also neutralizes the kappa and delta variants, preventing hospitalizations and deaths caused by them.

A booster dose of either of these vaccines is here shown to further improve antibody levels, even though the new vaccine contains the spike protein from B.1.351. “These data support clinical assessment of AZD2816 in vaccine naïve individuals as well as those previously vaccinated with AZD1222.”

*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.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.