Mutations in the original strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have resulted in the emergence of several variants. Some of these variants are more virulent with a higher rate of transmission as compared to the original SARS-CoV-2 strain that was first reported in Wuhan, China in 2019. Scientists have classified the SARS-CoV-2 variants into two categories of variants of concern (VoC) or variants of interest (VoI) based on their transmission and mortality rates.
SARS-CoV-2 VoCs such as the Alpha and Delta variants emerged in late 2020 and spring 2021, respectively. Both these variants have increased transmissibility and pathogenicity due to the mutation in the spike protein.
The Beta, Gamma, and Delta VoCs were found to partially evade the host’s immune response induced after natural infection or vaccination. This has led many to question the effectiveness of available vaccines developed against the spike protein of the original SARS-CoV-2 strain.
Study: SARS-CoV-2 preS dTM vaccine booster candidates increase functional antibody responses and cross-neutralization against SARS-CoV-2 variants of concern in non-human primates. Image Credit: Blue Planet Studio / Shutterstock.com
Modification of vaccine design in accordance with the circulating strain
In the influenza model, vaccines are modified yearly based on epidemiological data. This strategy has been implemented on SARS-CoV-2, where the parental vaccine (spike antigen) has been modified to contain the variants circulating as the dominant strain. This modification is currently being tested in a clinical trial (NCT04785144).
Knowing that immunity, by natural infection or immunization, wanes off and that the risk of antibody escape by emerging SARS-CoV-2 variants is rising, the key features of future vaccines will be the capacity to boost immunity for longer periods and provide broad protection against the virus and its variants.
Effectiveness of COVID-19 booster vaccines against SARS-CoV-2 variants
New research published on the bioRxiv* preprint server discusses the development of soluble prefusion-stabilized spike trimers (CoV2 preS dTM) comprising adjuvant AS03. This adjuvant is based on an oil-in-water emulsion consisting of α-tocopherol, squalene, and polysorbate. The AS03 not only induces robust antibody responses but also enhances vaccine durability and promotes heterologous strain cross-reactivity.
A prior study conducted by the same group of researchers revealed that CoV2 preS dTM-AS03 (D614) offered protection against the original SARS-CoV-2 strain by inducing the production of immunoglobulin G (IgG) antibodies. The human clinical trials had also shown that the CoV2 preS dTM21 AS03 successfully elicited robust neutralizing antibody responses in naïve subjects and were safe.
The present study evaluated a subunit vaccine booster in vaccinated macaques that were vaccinated with mRNA-LNP or subunit CoV2 preS dTM-AS03 Sanofi Pasteur vaccine candidates seven months earlier. The researchers analyzed various formulations regarding their ability to elicit cross-neutralization against VoC.
The formulations used in this study were AS03-adjuvanted parental (D614), bivalent (D614+B.1.351) CoV2 preS dTM, variant (B.1.351), and non-adjuvanted CoV2 preS dTM (B.1.351). The authors analyzed the NAb responses against the SARS-CoV-1, SARS-CoV-2, and the Alpha, Beta, Gamma, and Delta VoCs to determine the breadth of neutralization. For this investigation, they used a lentivirus-based pseudovirus neutralizing antibody (NAb) assay.
The current study reports that primed macaques, which were provided one dose of booster formulations, were found to exhibit higher and stable cross-NAbs that were effective against all SARS-CoV-2 VoCs (Alpha, Beta, Gamma, and Delta), as well as SARS-CoV-1. The non-adjuvanted CoV2 preS dTM B.1.351 vaccine formulation also significantly enhanced antibody response with broad neutralizing ability. At present, this vaccine candidate is under evaluation in Phase II and III clinical trials (NCT04762680 and NCT04904549).
The authors claim that this is the first report on the effectiveness of SARS-CoV-2 booster recombinant vaccine formulations showing positive results against the SARS-CoV-2 VoCs as well as SARS-CoV-1. It is important to point out that all tested booster vaccine formulations induced NAb titers with similar breadth. Hence, this immunogenicity model indicates no antigenic sin towards the original vaccine strain. Although all booster formulations were able to expand the breadth of neutralization, a more balanced neutralization profile was observed in monovalent B.1.351 or bivalent vaccine formulations.
When compared to the non-adjuvanted formulation, the adjuvant AS03 was associated with increased NAb titers against the original strain, VoCs, and SARS-CoV-1. These results are in line with previous studies, where AS03 adjuvantation consistently elevated the magnitude and breadth of the immune response.
This study revealed that a single dose of booster vaccine candidates could offer stable and prolonged protection against SARS-CoV-2, VoCs, as well as SARS-CoV-1. However, since the macaques in this study were not challenged, the researchers failed to determine the mechanistic correlates of protection against SARS-CoV-2 variants.
Another limitation of this study is the inclusion of a smaller number of animals of only four to five macaques per group. Also, the booster was assessed in messenger ribonucleic acid (mRNA)- and subunit-primed macaques only, and adenovirus vector vaccines were not considered.
In the future, more studies on the interval between the vaccine and booster dose are required. Additionally, the mechanism behind the increased cross-neutralization via boosters must be further studied.
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.