By Peter Katona, MD

Coronaviruses are single-stranded RNA viruses with large genomes and, until recently, consisted of the mild 229E, OC43, L69, and H53U1 strains, and the "novel" SARS and MERS strains. Sometime in late 2019, a third "novel" coronavirus called the "Wuhan" strain emerged. This began what we now know as the COVID-19 pandemic. With subsequent mutation, "variants of concern" soon emerged, starting with Alpha, and the most significant subsequently being Delta and then Omicron.

Mutations evolved and new strains replaced older variants. Now we are in the Omicron subvariant replacement phase. BA.1 was replaced by BA.2 and then BA.2 was replaced by BA.2.12.1. Starting in early 2022, the latest of these subvariants of concern became the BA.4 and BA.5 subvariants, originally described in South Africa. The earliest samples of BA.4 and BA.5 in the U.S. were collected on March 30 and March 29, respectively.

Each time a new variant comes along, it feels like we're starting from scratch all over again. How fast is the new variant spreading? What does the symptomatology and severity look like? While many questions remain about these new subvariants, below I review current insights into their transmissibility, disease severity, and survivability.

What We Know

Transmissibility

For any new variant to succeed, a number of things have to go right. We start with transmissibility with a high R0 (the number of people that can be infected for every case), but transmissibility alone is not necessarily enough. There is a minimum quantity of virus (viral load) needed to stay around to infect. What about replicating more quickly by binding more tightly to the lung's ACE2 receptor? There is variable environmental survivability in different climates and hosts.

BA.4 and BA.5 have high transmission rates in South Africa and elsewhere. Why South Africa? It may have to do with the local population's immunity, but there are countless potential factors at play. These variants might have arisen because of the percentage of people there that have either been infected or vaccinated; the new strains may have been hidden in parts of Africa in safe harbors of land poorly tracked that we have paid little attention to; there may have arisen a new animal reservoir; or a genetic mutation might have occurred in a single immunosuppressed individual.

Disease Severity

Severity of disease is another key factor impacting spread: does the variant cause just the right amount of clinical disease? If, for example, it causes too mild illness, it will keep people who can transmit the disease in wide circulation and burn out quickly; if it causes too much clinical disease there will not be enough virus left to continue transmission. Generally, BA.4 and BA.5 variants cause mild disease but spread in large numbers potentially because, unlike the Wuhan strain, which settles in the lungs, these newer strains seem to attach to the more benign upper nasal passages. As with other Omicron variants, BA.4 and BA.5 symptoms are generally mild, and may include fever, malaise, and loss of smell, although the prevalence of long-term symptoms (long COVID) is still being evaluated. Serious illness is rare but possible, especially in the unvaccinated.

Variant Survivability

Variant survivability also involves testing evasion, vaccine evasion, and response to therapeutics. Duration and degree of viral shedding is important, as is surviving longer in the air or moving more readily through it. Possibly even more important is the percentage of infected people who become asymptomatic silent shedders, and the length of the incubation period, as this provides more time to infect more people without detection. All of these are key ingredients of COVID-19 variant transmissibility. The incubation of the newer variants seems to be slightly shorter (2 to 3 days).

The bottom line is that BA.4 and BA.5 are very highly transmissible, cause little severe disease, and are responsive to boosters (although protection wanes), monoclonal antibodies, and antivirals.

Unfortunately, both BA.4 and BA.5 are capable of escaping immune protection induced by infection with earlier Omicron and other prior variants, earning them the term "stealth" viruses. The unvaccinated are even less likely to be protected against symptomatic infection with BA.4 or BA.5. Sera from vaccinated individuals performed better in in vitro studies done thus far, but protection derived from currently available vaccines wanes over time. Fortunately, the third COVID vaccine booster dose slows down infection, spread, and serious disease from older variants. The effect of a third and fourth dose on BA.4 and BA.5 is still being evaluated. A universal Omicron vaccine is in development, but the efficacy is thus far unknown.

Rapid Mutation

Why are all these mutations happening so fast? BA.4 and BA.5 seem to undergo occasional mutational "sprints," mutating as much as four times faster than the normal Omicron mutation rate. More mutations can lead to more transmission, more severe disease, or evasion of the immune response -- much like flu's mutations. This may explain not only the rapid spread but also the non-linear spread, as in superspreader events where many get infected but some don't. There's also been genome swap between BA.1 and BA.2, and between Delta and Omicron in a single patient, as in the XE and "Deltacron" strains, respectively. BA.2.12.1 also seems to share properties with Delta. This exchange is also likely to be identified with BA.4 and BA.5.

Further Research Is Needed

Many questions remain: Will one or both of these two new subvariants take over? How much long COVID do they cause? Will they start to compete or augment each other? Will they dissolve into a fifth or sixth benign human coronavirus strain as it happened in the 1800's with a strain affecting cows and humans, or cause another large wave with increasing serious disease and case numbers -- or something in between? Why the escalation in new subvariants now? Novel flu strains only emerged three times in the last century. It took only two mutations this time. In other words, are mutations -- which have always been around -- increasing in frequency?

What are the implications for re-infection and needing yet another vaccine dose? Does a fourth dose help, and if so, for how long? Will waste water surveillance with sequencing help us recognize an evolving process early? Will the proposed vaccine for all Omicron variants work? How effective are masks and mandates in a world of COVID fatigue and very high transmissibility? And finally, what's the best course of action to fight BA.4 and BA.5 now and keep us safe?

The answer is likely testing, appropriate masking, ventilating properly, and vaccinating, as well as continued excellent biological and public health research to answer the many remaining questions.

Peter Katona, MD, is a clinical professor of Medicine in Infectious Diseases at the David Geffen School of Medicine and adjunct professor of Public Health at the Fielding School of Public Health at UCLA.