As new cases of COVID-19 soar, experts warn about the newly emerged COVID subvariant BA.5, a sub-lineage of BA.2. Subvariants of Omicron BA.1 emerged in 2021, BA.2 in early 2022 and BA.5 came in April 2022. BA.5 dominates globally, replacing BA.2. The BA.1 and BA.2 attach the upper respiratory tract, whereas, the BA.5 damages the lower lungs, making BA.5 more fatal.

What makes subvariants more lethal?

Changes in the spike protein impact the disease severity because the spike protein allows the virus to attach and internalize its nucleic acid into target cells. Variants with more efficient attachment capabilities impact disease severity and enhances community spread. Thus, these mutated variants become the dominant virus form, (selection of the fittest). 

The BA.5 propensity for being the dominant form of the Omicron lineages, occurred because it had one amino acid substitution in the spike receptor binding domain of target cells (a L452R polymorphism). With this mutation, the BA.5 subvariant has an increase propensity to bind target cells and locate into the lower lung, resulting in greater severity of COVID compared to previous subvariants.

Omicron BA.5 invade cells through transmembrane serine protease 2 (TMPRSS2) pathway 

One route of infection by the various variants of the Omicron virus is through a transmembrane serine protease pathway (TMPRSS2). If this pathway is inhibited, all variants of the virus can internalize through an alternative pathway, endocytosis. However, endocytosis results in decreased infectivity rates, as seen in the Delta variant and the BA.5 variant. The BA.1 and BA.2 variants infectivity rates were less impacted. When the serine protease pathway is not inhibited, the BA.5 demonstrates increased lung infection and disease severity.

BA.5 variant affects immunity more than other variants 

Moreover, the BA.5 variant has a greater potential to escape antibodies.

It is a matter of concern that BA.5 induces strikingly less innate immunity (previously programmed immunity) from infected cells. In mouse studies, scientists have observed that this variant induces fewer inflammatory cytokines and chemokines. These are small protein molecules secreted by the immune cells to recruit additional “protective” immune cells to prevent the virus from spreading inside the body, which may be one way the BA.5 infection increases lung infection. 

Researchers found that Omicron BA.4/5 infection triggers highly cross-reactive neutralizing antibodies compared to Omicron BA.1. In unvaccinated people, the Omicron BA.4/5  infection elicits neutralizing antibodies that “destroy/neutralize the virus” and that these antibodies are highly cross-reactive for other variants of concern. Because of this discovery, second generation vaccine developed based upon Omicron BA.4 may elicit more cross-reactive neutralizing antibodies than current vaccines based on Omicron BA.1.

Efficacy of monoclonal antibodies against Omicron BA.5 subvariant 

A recent study on the efficacy of FDA approved monoclonal antibodies have shown that several of these monoclonal antibodies exhibited neutralization activity against BA.5  (Imdeimab, Cilgavimab, Bebtelovimab and Tixagevimab). Bebtelovimab has neutralization activity against all Omicron BA subvariants tested. However, in clinical use, combination therapy may not impact all variants. More clinical studies have to be conducted.

Previous infection with Omicron variants confers certain level of protection from Omicron BA.1 or BA.2 subvariant

A recent study highlights that prior BA.4/5 Omicron infection, was 80% effective at preventing BA.4/5 re-infection and more than 76% effective at preventing symptomatic reinfection.

On the other hand, previous infection with any pre-omicron variants had less impact of preventing BA.4/5 re-infection with an effectiveness of only 28% and re-infection with an effectiveness of around 15%.

Omicron BA.5 subvariant associated with higher odds of reinfection and vaccine breakthrough

A recent Omicron BA.5 report from Portugal indicates BA.5 subvariant is associated with vaccine breakthrough and significantly increased risk of reinfection regardless of the vaccination status. However, booster vaccination offers considerable protection against severity from BA.5 infection. The BA.5 variant is also associated with higher rate of hospitalization than BA.2 subvariant.

New vaccines for Omicron BA.5 subvariant

The BA.5 subvariant evades neutralizing antibody responses even after 3-doses of  the current vaccination developed against BA.1.1 infection Therefore, there was an urgent need of designing boosters that work against newly emerged BA.5 subvariant.

Moderna has designed a bivalent booster known as mRNA-1273.241. Compared to currently authorized Covid boosters (neutralizing titres were 458), the newly designed booster (neutralizing titres were 776) demonstrates significantly higher neutralizing antibody response against BA.5, as well as other Omicron subvariants. Moderna has completed the regulatory submission for their newly designed booster in the UK, Europe, and Australia.

After Moderna, Novavax designed an RNA vaccine (NVX-CoV2373) which is effective against BA.5 subvariant. After three doses of the vaccine, scientists reported enhanced neutralization not only against BA.5 but also BA.1 and BA.4.

Further reading

3. Desingu and Kumaresan (2022) The emergence of Omicron lineages BA.4 and BA.5, and the global spreading trend. J Med Virol. 2022 Jun 30. doi: 10.1002/jmv.27967.
4. Aggarwal, et al.(2022) SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics medRxiv. 2022    doi:10.1101/2022.07.07.22277128. https://www.medrxiv.org/content/10.1101/2022.07.07.22277128v1
5. Kislaya I, et al. (2022) SARS-CoV-2 BA.5 vaccine breakthrough risk and severity compared with BA.2: a case-case and cohort study using Electronic Health Records in Portugal. medRxivdoi: doi.org/10.1101/2022.07.25.22277996. https://www.medrxiv.org/content/10.1101/2022.07.25.22277996v1
6. Moderna’s Omicron-Containing Bivalent Booster Candidate, mRNA-1273.214, Demonstrates Significantly Higher Neutralizing Antibody Response Against Omicron Subvariants BA.4/5 Compared To Currently Authorized Booster- Moderna. https://investors.modernatx.com/news/news-details/2022/Modernas-Omicron-Containing-Bivalent-Booster-Candidate-mRNA-1273.214-Demonstrates-Significantly-Higher-Neutralizing-Antibody-Response-Against-Omicron-Subvariants-BA.45-Compared-To-Currently-Authorized-Booster/default.aspx
7. Richardson, S. et al. (2022) “SARS-CoV-2 BA.4 infection triggers more cross-reactive neutralizing antibodies than BA.1”. bioRxiv. doi: 10.1101/2022.07.14.500039. https://www.biorxiv.org/content/10.1101/2022.07.14.500039v1
8. Takashita E, et al. Efficacy of antibodies and antiviral drugs against omi- cron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. doi: 10.1056/NEJMc2207519 https://www.nejm.org/doi/full/10.1056/NEJMc2207519