Friday, May 19, 2023

WHO Recommends Switching To A Monovalent XBB based COVID Vaccine




Three weeks ago, in CDC Nowcast: Recombinants Rule, we looked at the near total domination of emerging XBB.*.* (recombinant) SARS-CoV-2 variants in the United States. Remarkable, because a little over a year ago, there was still scientific debate over their very existence (see A COVID Recombination Review).

So far, we've not seen any evidence that these XBB recombinant variants cause any greater severity of illness than their Omicron ancestors, but they do appear to be gaining in transmissibility and immune evasion over time. 

All of the COVID vaccines currently used around the world are either based on either the original 2020 strain - or are bivalent vaccines with an added BA.1 or BA.4/BA.5 component - all of which are pretty much extinct in the wild today. (Full disclosure: Since existing vaccines may still protect against severe illness, I elected to get my 2nd bivalent booster earlier this month).  

Despite decrees by governments around the world that the crisis has passed - as community immunity (from either vaccination, prior infection, or both) wanes - there is a very real risk of seeing new (potentially serious) waves of COVID in the months and years ahead. 

Yesterday the World Health Organization released the results of a consultation of their Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) which recommends  - based on limited data - to a switch to a monovalent vaccine based on XBB.1.5 or XBB.1.6.

Selecting the next vaccine formulation for a virus that mutates as rapidly as COVID is an unenviable task. 

There are no guarantees that XBB.1.5/1.6 will still reign supreme 3 or 6 months from now, there is little direct evidence of the effectiveness of XBB derived vaccines in humans, and the willingness of the public to embrace yet another vaccine is unknown. 

Due to its length and technical nature I've only posted some excerpts, so  follow the link to read the WHO statement in its entirety. 

Statement on the antigen composition of COVID-19 vaccines
18 May 2023
Reading time: 6 min (1616 words)
The WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) continues to meet regularly to assess the implications of SARS-CoV-2 evolution for COVID-19 vaccine antigen composition and advise WHO on whether changes are needed to the antigen composition of future COVID-19 vaccines.


The TAG-CO-VAC recognizes and reiterates that currently approved COVID-19 vaccines, including those based on the index virus, continue to provide substantial protection against severe disease and death, which is the primary objective for COVID-19 vaccination. Currently approved COVID-19 vaccines should continue to be used in accordance with the current WHO SAGE Roadmap, published in April 2023. Notwithstanding the protection against severe disease, protection against symptomatic disease is limited and less durable. New formulations of COVID-19 vaccines are needed to improve protection against symptomatic disease.


Summary of available evidence

In the fourth year of the pandemic, there is high seroprevalence in the global population as a result of vaccination and/or infection, and immunological profiles against SARS-CoV-2 are highly heterogeneous (i.e. individuals have been infected with different variants and/or vaccinated using a variety of vaccine platforms).

There continues to be substantial genetic and antigenic evolution of the spike protein of SARS-CoV-2, and the evolutionary trajectory continues to diverge from the index virus. Despite increasing gaps in genomic surveillance globally, the available sequencing data indicates that the index virus and other early variants (e.g., Alpha, Beta, Gamma and Delta) are no longer detected in humans.

As of May 2023, the XBB.1 descendent lineages currently predominate globally (i.e., XBB.1.5, XBB.1.16, XBB.1.9).

As described in the WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution 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 highly 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 date.

Estimates of VE against currently circulating SARS-CoV-2 variants, including XBB.1 descendent lineages, are very limited in terms of the number of studies, vaccine products evaluated, and populations assessed; some studies show similar VE against BA.5 descendent and XBB.1 descendent lineages, while others suggest reduced VE during periods of predominance of XBB.1 descendent lineages.

Sera from individuals 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 show substantially lower neutralizing antibody titers against XBB.1 descendent lineages, as compared to titers specific for the antigens included in the vaccine. Individuals with hybrid immunity due to any SARS-CoV-2 infection show higher neutralizing antibody titers against XBB.1 descendent lineages as compared to responses from vaccinated individuals who had no evidence of infection.

There is in vitro evidence that immune imprinting, which is a phenomenon in which B cell memory recall responses towards previously encountered antigen reduce the response to new antigens, may be occurring. However, based on observational epidemiological studies to date, the clinical impact remains unclear.

Preclinical data shared confidentially with the TAG-CO-VAC by vaccine manufacturers show that vaccination with XBB.1 descendent lineage-containing candidate vaccines (including XBB.1.5) elicits higher neutralizing antibody responses to currently circulating SARS-CoV-2 variants, compared to responses elicited by currently approved vaccines.

Recommendations for updates to COVID-19 vaccine antigen composition

There is ongoing and considerable genetic and antigenic evolution of SARS-CoV-2, high seroprevalence and heterogeneous population immunity to SARS-CoV-2. As current WHO SAGE policy specifies, vaccination programmes should continue to complete the primary series and booster dose(s) for high priority and medium priority groups. Furthermore, the WHO Global COVID-19 Vaccination Strategy, published in July 2022, also calls for vaccines with improved durability and breadth of protection.

Updates to vaccine antigen composition may enhance vaccine-induced immune responses to circulating SARS-CoV-2 variants, consistent with the previous statement by the TAG-CO-VAC published in June 2022.

As of May 2023, XBB.1 descendent lineages predominate SARS-CoV-2 circulation globally. In order to improve protection, in particular against symptomatic disease, new formulations of COVID-19 vaccines should aim to induce antibody responses that neutralize XBB descendent lineages. One approach recommended 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.
Given the small genetic and antigenic differences from XBB.1.5, XBB.1.16 (e.g., hCoV-19/USA/MI-CDC-LC1038976/2023, GenBank: OQ931660 GISAID: EPI_ISL_17619088) may be an alternative. The spike antigens of both of these lineages are genetically and antigenically very closely related, with only two amino acid differences between XBB.1.5 and XBB.1.16 (E180V and T478R). Other formulations and/or platforms that achieve robust neutralizing antibody responses against XBB descendent lineages can be considered.

While currently approved COVID-19 vaccines, including those based on the index virus, continue to provide protection against severe disease, the TAG-CO-VAC advises moving away from the inclusion of the index virus in future formulations of COVID-19 vaccines. This is based on the following reasons:
  • the index virus and antigenically closely related variants no longer circulate in humans;
  • the index virus antigen elicits undetectable or very low levels of neutralizing antibodies against currently circulating SARS-CoV-2 variants, including XBB descendent lineages;
  • inclusion of the index virus in bi- or multivalent vaccines reduces the concentration of the new target antigen(s) as compared to monovalent vaccines, which may decrease the magnitude of the humoral immune response;
  • and immune imprinting due to repeated exposure to the index virus may reduce immune responses to new target antigen(s).

Vaccine selection is a game of incomplete information, and sometimes you have to make the best scientific assumptions you can, and hope they pan out.  

I'm just glad it isn't my job to decide.