The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) continues to meet often to evaluate the effects of SARS-CoV-2 evolution on the antigen composition of the COVID-19 vaccine and provide recommendations to WHO on whether adjustments to the antigen makeup of future COVID-19 vaccine are required.
The TAG-CO-VAC announced in April 2023 that the advisory group would meet at least twice in 2023: once in May 2023 and once again, roughly six months later. At each meeting, suggestions will be made regarding either maintaining the present vaccine composition or taking modifications into consideration.
Based on the kinetics of vaccine-derived immunity and the requirement for ongoing monitoring of the evolution of SARS-CoV-2, the TAG-CO-VAC will change the frequency of evidence review as needed. The TAG-CO-VAC gathered on May 11 and 12, 2023, to discuss the genetic and antigenic evolution of SARS-CoV-2, the efficacy of the vaccines already on the market against SARS-CoV-2 variants in circulation, and the implications for the COVID-19 vaccine antigen composition.
The goal of an update to the COVID-19 vaccine antigen composition, as previously stated by the TAG-CO-VAC, is to improve vaccine-induced immune responses against circulating SARS-CoV-2 variants. This statement and the change-recommendation are meant to serve as guidance for all vaccine producers as they develop future COVID-19 vaccine formulations.
The main goal of COVID-19 immunization is to prevent serious illness and death, and the TAG-CO-VAC acknowledges and reiterates that already licensed COVID-19 vaccines, including those based on the index virus, continue to offer significant protection against these outcomes. The use of COVID-19 vaccinations that are currently approved should continue in compliance with the most recent WHO SAGE Roadmap, which was released in April 2023. Despite the defense against serious illness, the defense against symptomatic illness is weaker and less long-lasting. Improved COVID-19 vaccine formulations are required to increase protection against symptomatic illness.
Evidence Reviewed
The TAG-CO-VAC looked at both published and unpublished evidence, which included: (1) SARS-CoV-2 evolution, including the genetic and antigenic traits of earlier and modern SARS-CoV-2 variants, including XBB.1 descendent lineages, and their effects on cross-neutralization and cross-protection following vaccination and/or infection; (2) Vaccine effectiveness (VE) of currently approved vaccines during periods of XBB.1 descendent lineage circulation; (3) Antigenic cart
The data annex that goes along with this report contains more information on the publicly accessible data that the TAG-CO-VAC reviewed. No private or confidential information is displayed.
The TAG-CO-VAC is aware of the limitations of the information currently available:
Although the trajectory of subsequent SARS-CoV-2 development suggests that, in the near future, XBB will probably serve as the progenitor of SARS-CoV-2 variants, the timing, particular mutations and antigenic features, and the potential public health hazards of future variants are still unclear;
There is a paucity of information on the cross-reactivity (breadth) of immune responses induced by the SARS-CoV-2 variants currently in circulation. The most recent variations, XBB.1 or XBB.1.5, have the majority of the clinical and preclinical data available, while more recent variants of interest or variants under monitoring have very little information;
Limited information is available on immunological reactions over time following infection with SARS-CoV-2 variants that are currently circulating;
There are numerous levels of immunological protection induced by infection and/or vaccination, even while neutralizing antibody titers have been demonstrated to be significant in protection from SARS-CoV-2 infection and in estimations of vaccine effectiveness. There is a lack of information on other components of the immune response, such as cellular immunity, and neutralizing antibodies are basically the only type of information available on the immunological response unique to XBB.1 descendant lineages;
Information on the defense provided by hybrid immunity, or the combination of infection- and vaccination-induced immunity, is generally acquired from groups that mainly received an mRNA booster dose;
Current COVID-19 vaccines, including those based on index viruses and bivalent mRNA vaccines, have minimal information on their effectiveness (VE) against XBB descendant lineages. Data on candidate vaccines that have an XBB are only available for mRNA vaccines, which only have one descendent lineage circulation. Model animals are the only descendent lineage allowed. The TAG-CO-VAC considered a summary of the evidence that is currently available and provided WHO with the recommendations that follow.
a list of the available proof.
The fourth year of the pandemic has seen a high seroprevalence in the world’s population as a result of vaccination and/or infection, and immunological profiles against SARS-CoV-2 are highly heterogeneous (i.e., people have been exposed to various SARS-CoV-2 variants and/or vaccinated using various vaccine platforms).
The spike protein of SARS-CoV-2 is still undergoing significant genetic and antigenic evolution, and its evolutionary path is still diverging from that of the index virus. The available sequencing data shows that the index virus and other early variations (such as Alpha, Beta, Gamma, and Delta) are no longer found in people, despite widening gaps in genomic surveillance internationally.
The XBB.1 descendent lineages (XBB.1.5, XBB.1.16, XBB.1.9) currently dominate internationally as of May 2023.
According to the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution’s XBB.1.5 Updated Risk Assessment and the XBB.1.16 Initial Risk Assessment, XBB descendent lineages, including XBB.1.5 and XBB.1.16, are extremely immune evasive, with XBB.1.5 being one of the SARS-CoV-2 variants with the greatest magnitude of immune escape from neutralizing antibodies to it.
In terms of the number of studies, vaccine products, and populations assessed, estimates of VE against currently circulating SARS-CoV-2 variants, including XBB.1 descendent lineages, are very scarce. While some studies indicate comparable VE against BA.5 descendent and XBB.1 descendent lineages, others suggest lower VE during times when XBB.1 descendent lineages predominated.
When compared to titers specific for the vaccine’s antigens, sera from people who have received two, three, or four doses of index virus-based vaccines or a booster dose of a bivalent (BA.1- or BA.4/5-containing) mRNA vaccine exhibit significantly lower neutralizing antibody titers against XBB.1 descendent lineages. Any SARS-CoV-2 infection results in hybrid immunity, which is indicated by greater neutralizing antibody titers against XBB.
Vaccinated people’s responses were superior to those of those who showed no signs of illness and had only one descendent lineage.
Immune imprinting, which is a phenomena in which B cell memory recall responses to previously met antigen limit the response to new antigens, may be taking place, according to in vitro studies. The clinical impact, however, is yet unknown based on observational epidemiological research conducted to far.
Manufacturers of vaccines have provided the TAG-CO-VAC with confidential preclinical data that demonstrate that vaccination with candidate vaccines that contain XBB.1 descendent lineage antigens (including XBB.1.5) results in stronger neutralizing antibody responses to SARS-CoV-2 variants that are currently circulating than vaccination with vaccines that are currently approved.
Updates to the COVID-19 vaccine antigen mix are suggested
High seroprevalence and diverse population immunity to SARS-CoV-2, as well as ongoing and significant genetic and antigenic change, are all present. For high priority and medium priority populations, vaccination programs should continue to finish the primary series and booster dose(s), as stated in the most recent WHO SAGE policy. Additionally, the WHO Global COVID-19 Vaccination Strategy, which was released in July 2022, advocates for vaccines with increased robustness and coverage.
According to the earlier TAG-CO-VAC announcement published in June 2022, updates to vaccine antigen composition may improve vaccination-induced immune responses to circulating SARS-CoV-2 variants.
As of May 2023, SARS-CoV-2 circulation worldwide is dominated by lineages descended from XBB.1. New COVID-19 vaccine formulations should attempt to elicit antibody responses that neutralize XBB descendant lineages in order to enhance protection, particularly against symptomatic illness. One strategy advocated by TAG-CO-VAC is the use of a monovalent XBB.1 descendent lineage, such as XBB.1.5 (e.g., hCoV-19/USA/RI-CDC-2-6647173/2022, GenBank: OQ054680.1, GISAID: EPI_ISL_16134259 or WHO Biohub: 2023-WHO-LS-01, GenBank: OQ983940, GISAID EPI_ISL_16760602) as the vaccine antigen. XBB.1.16 (e.g., hCoV-19/USA/MI-CDC-LC1038976/2023, GenBank: OQ931660 GISAID: EPI_ISL_17619088) may be an option due to its minor genetic and antigenic variations from XBB.1.5. With only two amino acid changes between XBB.1.5 and XBB.1.16 (E180V and T478R), the spike antigens of both of these lineages are very closely linked genetically and antigenically.
It is possible to take into account additional formulations and/or platforms that produce potent neutralizing antibody responses against XBB descendant lineages.
The TAG-CO-VAC suggests avoiding using the index virus in future COVID-19 vaccine formulations, even though presently licensed COVID-19 vaccines, including those based on the index virus, continue to offer protection against serious illness. Based on the following, this is true: Antigens from the index virus elicit undetectable or extremely low levels of neutralizing antibodies against currently circulating SARS-CoV-2 variations, including XBB descendant lineages; the index virus and antigenically closely related variants no longer infect humans; In comparison to monovalent vaccines, the inclusion of the index virus in bi- or multivalent vaccines diminishes the concentration of the new target antigen(s), which may reduce the strength of the humoral immune response; Moreover, frequent exposure to the index virus may result in immunological imprinting, which may weaken immune responses to fresh target antigen(s).
Additional data needs and concerns
The TAG-CO-VAC strongly encourages the generation of data on immune responses and clinical endpoints in humans who receive a COVID-19 vaccine with an updated composition, across different vaccine platforms, as well as additional data on the effectiveness of current COVID-19 vaccines against circulating SARS-CoV-2 variants, given the limitations of the evidence upon which the recommendations above are based and the expectation that the virus evolution will continue.
Additionally, in line with the WHO Global COVID-19 Vaccination Strategy, which was released in July 2022, the TAG-CO-VAC continues to promote the ongoing development of vaccines that boost mucosal immunity since they may improve protection against infection and decrease transmission of SARS-CoV-2. Last but not least, it is critical that international organizations, governments, and vaccine producers continue working together to provide equitable global access to vaccine(s) with an updated antigen composition as soon as they become available.
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