Will Omicron BA.5 Be the Last of the COVID Variants?

Creative rendition of SARS-CoV-2 virus particles. Note: not to scale. NIAID [shorturl.at/hHKWY]

On January 20, 2020, the first case of COVID-19 emerged in the United States. More than 30 months on, the pandemic is still considered ongoing.

COVID-19, whose official name is coronavirus disease 2019, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). The COVID-19 pandemic’s continuation and severity are mainly due to the virus’s fast mutations and its many variants. As a type of RNA virus, SARS-CoV-2 has a very high mutation rate. This is because the RNA polymerase that replicates the virus’s genes doesn’t have excellent proofreading skills. However, this actually helps the virus by allowing its variants to find new hosts and escape immunity induced by vaccination or previous in

fection. As a result, during the spreading of the virus, different geographic areas have generated genetically distinct variants.

In June 2021, the World Health Organization (WHO) started using the Greek alphabet to describe “variants of interest,” which are SARS-CoV-2 virus strains that are considered more dangerous than earlier forms of the virus. These variants are typically considered important due to their increased transmissibility, increased virulence, or the COVID-19 vaccines’ reduced effectiveness against them.

Prior to the WHO rolling out these rules, researchers around the globe came up with their own lineage naming rules to facilitate their genome sequencing of the virus. As SARS-CoV-2 is a rapidly evolving virus with a high rate of lineage turnover, some Western scientists used the letter A to denote the ancestral type, which is the Wuhan original strain, and the letter B to denote a derived lineage. Many variants of interest, such as alpha, beta, delta, and omicron, belong to lineage B.

The current variants of concern, or more precisely, subvariants (i.e. subsidiary variants) of concern, are BA.4 and BA.5. As of August 13, 2022, BA.5 cases accounted for 88.8 percent of all COVID-19 cases in the United States, followed by BA.4 (5.3 percent) and the latter’s own newer version BA4.6 (5.1 percent). From the statistics, we can see that BA.5 is more transmissible than BA.4, but so far, scientists haven’t gained an understanding as to why this is the case, as both subvariants are very similar.

BA.4 and BA.5 Are Currently the Most Contagious COVID-19 Subvariants, With Higher Pathogenicity

As BA.4 and BA.5 are derived from BA.2, they’re very similar to the latter. According to a preprint study on MedRxiv, the spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2. However, each of these subvariants has its own different mutations from BA.2 in other areas of the virus.

BA.4 and BA.5 are more contagious than any other subvariants of the SARS-CoV-

2 virus. According to a Japanese study, the Re value of BA.4 and BA.5 is 1.2 times higher than that of BA.2. The Re value, also known as the Rt value, is a virus’s effective reproduction number, which represents the number of people in a population that can be infected by an individual at any specific time. This number represents a virus’s transmissibility. BA.4 and BA.5 are 18.3 times more infectious than BA.2, and are currently the subvariants with the fastest increasing transmission rate.

BA.2 used to be the dominant subvariant around the globe, and BA.4 and BA.5 have rapidly replaced BA.2 in many countries, including the United States, since April 2022.

Furthermore, BA.4 and BA.5 appear to have higher pathogenicity than BA.2.

In a preprinted study of animal models, some Japanese researchers infected some wild-type Syrian hamsters with 105 plaque-forming units of BA.4, BA.5, or BA.2 subvariants and performed histopathological analysis. They discovered that inflammation, hemorrhage, congestion, and alveolar damage were significantly higher in the lungs of BA.4 and BA.5-infected hamsters than in BA.2-infected ones. Therefore, BA.4 and BA.5 are more pathogenic than BA.2.

So far, the symptoms of BA.4 and BA.5 appear to be mostly upper-respiratory, including sore throat, running nose, incessant cough, headache, and fatigue, which are similar to the typical Omicron symptoms.

BA.4 and BA.5 Are Presently the Most Vaccine-Evasive COVID-19 Subvariants

In comparison with the other subvariants, BA.4 and BA.5 are masters at bypassing immunity from a previous infection or vaccination. So people who were formerly infected by other Omicron subvariants can also get re-infected.

As the existing COVID-19 vaccines have been developed based on the original strain. Their protection against Omicron has been significantly reduced, and their protection against BA.4 and BA.5 may be even lower.

In the preprinted Japanese study, by analyzing peripheral blood sera from some convalescents, the researchers discovered that the serum neutralizing antibody titers with BA.4 and BA.5 in those patients who had had two to three doses of COVID-19 vaccines and later had a breakthrough infection by BA.1, were significantly lower than those with BA.2. That is, the combination of full-course vaccination and breakthrough infection cannot protect people from BA.4 or BA.5 infection.

Back on June 30, 2022, the Food and Drug Administration (FDA) warned that the effectiveness of existing COVID-19 vaccines had started to wane against Omicron variants, including BA.4/5. According to the FDA’s statement, “post-authorization observational studies have shown that effectiveness of primary vaccination wanes over time against certain variants, including Omicron.”

BA.4/5 May Bypass Immunity Induced by Previous Infection with COVID-19

Is the immunity gained from a previous COVID-19 natural infection effective against BA.4/5? The answer is: it depends. Although BA.4 and BA.5 subvariants are highly immune-evasive, the immunity acquired from an Omicron infection can still be helpful in protecting people against them. However, if the infection was by a different strain, then the protection offered by the infection-induced immunity may not be great.

The following studies shed some light on this issue.

According to the latest data from the UK Health Security Agency, similar to the pandemic situation in the United States, BA.5 has become the dominant subvariant in the UK, accounting for almost 80 percent of all COVID-19 cases.

The UK Health Security Agency has been carrying out a systematic cohort study (pdf) called the SARS-CoV-2 Immunity and Reinfection EvaluatioN (SIREN).

The participants of this study are more than 44,000 National Health Service healthcare workers from 135 hospitals across the UK. These participants are under active follow-up and undergo asymptomatic SARS-CoV-2 PCR testing every 2 weeks. The cohort had a high seropositivity rate of 30 percent before the second wave hit and is now over 95 percent vaccinated.

The incidence of new infections and reinfections is evaluated in this cohort. Reinfection is defined as a new infection (i.e. PCR positive) 90 days after a prior one.

The graph shows the fortnightly trends of PCR positivity in the SIREN cohort study, and they appear to be consistent with the trends of the alpha, delta, BA.1, BA.2, and other COVID variants. Starting from mid-May 2022, due to the prevalence of BA.4/BA.5, the trend has been going upwards again.

According to the graph, there has been an increase in both primary infection and reinfection rates since May 2022. The increase in primary infection rates indicates that Omicron and its subvariants have significantly enhanced transmission rates, resulting in a large number of infections. The increase in reinfection rates indicates that people who were previously infected can still get infected right now. Therefore, the immunity from natural infection doesn’t necessarily offer protection against BA.4 and BA.5. Infection-induced immunity’s effectiveness in preventing BA.4/5 infection depends on the strain of the previous infection.

Another preprint study was conducted by a team of researchers from Weill Cornell Medicine-Qatar in Doha. According to the study, young and middle-aged adults who were previously infected with earlier subvariants of Omicron may have substantial protection against BA.4 and BA.5. However, for the people that were infected with a variant that appeared before Omicron, they would not have similar protection against reinfection with BA.4 or BA.5.

This preprint study used the S-gene “target failure” (SGTF) infections to estimate the effectiveness of previous infections with SARS-CoV-2 in preventing reinfection with Omicron BA.4/BA.5 subvariants. The SGTF status provides a proxy for BA.4/BA.5 infections.

It was discovered that infection with a pre-Omicron variant prevented reinfection by BA.4 or BA.5 with an effectiveness rate of 28.3 percent, and prevented symptomatic reinfection with an effectiveness rate of 15.1 percent. This is because first, a long time has passed since the prior infection; and second, the virus has mutated a lot since then.

The study also found that a previous Omicron infection prevented reinfection by BA.4 or BA.5 with an effectiveness rate of 79.7 percent, and prevented symptomatic reinfection with an effectiveness rate of 76.1 percent. This is because first, the previous infection is relatively recent; and second, the viral mutations have not been large.

Therefore, regardless of previous COVID-19 infections, it is wise for us to maximize our own anti-viral immunity.

BA.4 and BA.5 Subvariants Are Built to Escape Immunity

The BA.4 and BA.5 sub-lineages are the most transmissible and immune-evasive strains of the COVID-19 virus to date. What are the differences between them and the other subvariants that have given them their ability to escape immunity?

As aforementioned, BA.4 and BA.5 subvariants have identical spike sequences. In comparison with the BA.1 and BA.2 sub-lineages, they have L452R and F486V mutations and the R493Q reversion in the spike receptor binding domain (RBD), which is likely most targeted by neutralizing antibodies.

The production of neutralizing antibodies can be triggered by infection or vaccination. They can result in lifelong immunity to certain viruses. A neutralizing antibody can stop a pathogen from infecting the body by preventing the molecules on the pathogen’s surface from entering the human cells. As in the case of all enveloped viruses (i.e. the virus cells are inside a lipid membrane), neutralizing antibodies block the attachment of a SARS-CoV-2 virus to the cell and its entry into the cell to infect it.

Some viruses are able to evade neutralizing antibodies by having regular mutations. As a result, the antibodies can no longer recognize them. The BA.2, BA.4, and BA. 5 subvariants all carry a mutation in amino acid L452 of their spike protein. These L452 mutations facilitate their escape from some antibodies directed to certain regions of the receptor-binding domain, and such mutations have also caused several subvariants to appear.

The F486V mutations found in BA.4/5 also facilitate their escape from certain antibodies, whereas the R493Q reversion mutation restores receptor affinity (i.e. strength of the binding) and the fitness of BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively generating more subvariants that are not only more transmissible but also more evasive to antibodies.

According to Christian Althaus, a computational epidemiologist at the University of Bern, their capacity to infect people who were immune to earlier forms of COVID-19 strains has given rise to the prevalence of the BA.4 and BA.5 substrains.

Will BA.4 and BA.5 Sub-lineages Be the Last Subvariants?

The COVID-19 pandemic is entering its fourth year. People around the globe are hoping to see the light at the end of the tunnel. Then, will BA.4 and BA.5 subvariants be the last of their kind?

The answer is: no. It’s almost certain that the virus will continue to mutate and persist.

According to Eric Topol, professor of molecular medicine at the Scripps Research Institute in California, “We know BA.5 is not where this ends, unfortunately. We have further variants to work through for an indeterminate period of time.”

Kei Sato, a virologist at the University of Tokyo, also holds the same view. He says, “Nobody can say BA.4/5 is the final variant. It is highly probable that additional Omicron variants will emerge.”

Already, a new variant, BA.2.75, has emerged and is spreading rapidly in India. Many medical experts believe that it’s another super-contagious Omicron mutant, and virologists fear that it will fuel a new wave of cases around the world. It has been given the nickname “Centaurus” by social media users.

So far, BA.2.75 has been detected in over 20 countries, with India being hit the hardest. According to the Indian authorities’ statistics, BA.2.75 is now behind two thirds of the new COVID-19 cases in India. However, it hasn’t dramatically increased the country’s COVID-related hospitalization or death rate.

As the BA.2.75 subvariant is still evolving, it may develop more immune-evading mutations in the coming weeks. Some BA.2.75 sequences also have L452R mutations, which enhance the subvariant’s ability to re-infect people.