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The BA.5 Omicron Subvariant: The Worst Coronavirus Yet?

Variants of Concern

SARS-CoV-2 coronavirus

The coronavirus has been evolving rapidly over the past 6 months. (Electron microscope picture from the NIAID. The protrusions are the spike proteins the virus uses to infect cells).

Many variants of the SARS-CoV-2 coronavirus have been found, but since the Delta variant showed up in Oct  2020, only six have been considered “variants of concern“. Today, only one lineage of variants of concern – the Omicron variants and subvariants – is being watched now. 

Variants of concern increase transmissibility, produce a more severe disease, are better at evading the antibody response, are not knocked down as well by treatments or vaccines, or are harder to detect.

(Thankfully, no “variants of high consequence“, which produce increased rates of hospitalization/death, a significant reduction in vaccine effectiveness, and/or may be more difficult to detect, are circulating now.)

A Mutation Machine

Last year I read an op-ed that suggested that the coronavirus was probably close to exhausting its ability to mutate. Instead, with the emergence of the Omicron virus, it’s turned into a mutating machine. At the beginning of this year, BA.1 Omicron variant hit the U.S. and other countries hard – producing the most coronavirus infections ever.

By April, though, the BA.1 variant had been supplanted in the U.S. by the BA.2 variant and had become the dominant coronavirus variant around the world. The BA.2 variants’ stay at the top of the coronavirus food chain, was brief, however. By May – just one month later – the BA.2.12.1 subvariant had become dominant in the U.S. By July, the virus had taken another big mutational leap – the BA.4/5 variants were now dominant

At every step, the virus has become more and more transmissible: BA.2 was 30% more transmissible than the very contagious BA.1, and BA.2.12.1 and BA.4 and BA.5 are more transmissible yet.

As our attention has waned, as life has gotten pretty much back to normal and as mask wearing has plummeted, the coronavirus virus has been mutating like mad.

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The Latest “Variant of Concern” is a Doozy

In The BA.5 Story, Eric Topol M.D. lays out what he calls “the worst version of the virus that we’ve seen”. Topol is the real deal. A cardiologist, scientist, and author, Topol is the founder and director of the Scripps Research Translational Institute, and a professor of Molecular Medicine at The Scripps Research Institute. He’s published over 1,200 peer-reviewed articles, led clinical trials in dozens of countries, and is one of the top 10 most cited researchers in medicine. In 2016, he received a $207 million NIH grant to co-lead the Precision Medicine Initiative

He’s quite worried about BA.5 and what will inevitably follow it.

A New Virus Altogether?

The BA.5 variant first appeared in South Africa where it took one month for cases to rise from 1,000/day to 10,000/day. Hospitalizations and deaths did increase but not to previous levels. Next, BA.5 moved onto Portugal where, despite high vaccination rates, hospitalizations neared their previous Omicron peak. The New York Times noted that wherever the BA.5 variant has been able to settle in for a while, it’s produced a significant increase in hospitalizations.

CDC community transmission coronavirus

With regards to community transmission – the CDC on July 6th reported that the U.S. is back in the red again.

Since then, it’s been moving fast.  A month ago, BA.5 accounted for only 10% of cases in the U.S. Now it’s the dominant variant in the U.S., Canada, the U.K., and Europe. The 15% U.S. positivity rate – which tracks the percentage of positive test results – indicates the variant is spreading fast. The CDC estimates that the level of community transmission is high in more than 87 percent of U.S. counties and remains substantial or higher in 93% percent of counties. Basically, the U.S. is back to being almost all red. Across the world, cases have spiked 30% in two weeks We should know the impact it will have in the U.S. over the next month or so.

The earlier Omicron variants were more contagious but less severe because they were more likely to infect the upper respiratory tract (nose, sinuses, larynx) than the lungs. ( Anyone believing that the earlier variants were benign should read what happened to Aaron Teasdale – an adventure traveler and writer.) A recent report, however, found that the BA.4/.5 subvariants have evolved to target the lungs again – possibly making them more dangerous.

Immune Escape Artist

The BA.5 subvariant takes, as Topol puts it, “immune escape, already extensive, to the next level.” BA.5 is also far more transmissible than subvariants that came before it (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4).

Topol shows in a series of diagrams just how different BA.5 is. Genetically, the Omicron created a branch of its own. Then the BA.4 and BA.5 subvariants created new branches off that branch. Their spike proteins – the part of the virus used to get into our cells – are simply off the charts different from even the past BA variants. Some of those genetic mutations extend to other parts of the virus as well.

Multiple studies have shown that the BA.4/BA.5 variants produce the lowest levels of neutralizing antibodies in humans yet. Introducing the BA.5 variant to a hamster produced the most severe disease yet.

Antigenic distance

With regards the antigenic distance or the differences that have evolved in the genetic makeup of the spike protein that the virus uses to infect the cells – BA.4/5 are off the charts different.

With regard to its “fitness” – a term used to assess how fast the virus is reproducing, and how well it’s able to evade the immune system – BA.5 is basically off the charts more fit as well.

Fitness Coronavirus variants

A recent report from the Kirby Institute in Australia indicates that BA.5 is more like the Delta variant as regards infectivity (i.e. it’s more able to infect cells.) as well. With regards to “fitness” or the ability of the virus to reproduce and evade the immune system – the early BA variants that produced the most death and disease yet – were monumentally more fit than the earlier variants. BA.4/5 – not seen in this chart are even more fit.

BA.5 is so genetically different from previous iterations of the SARS-CoV-2 virus that one researcher has called for it be given its own name – SARS-CoV-3.

Hospitalizations and Deaths Still Low in the U.S.

The good news, of course, is that hospitalizations and deaths are still far below the January peak of this year, and it doesn’t seem that anyone expects that kind of peak again.  The subvariant is so different, though, that it’s hard to know exactly what will happen.

Given that vaccine effectiveness against hospitalization and death dropped from 95% for the Delta variant to 80% for the initial Omicron variant, it’s reasonable to assume that’s it going to drop more with BA.4/BA.5. People who are unvaccinated still make up a lion’s share of deaths, but the percentage of vaccinated people – particularly in the elderly – who are dying has increased.

The boosters still seem to be helping, however. The California Department of Public Health recently reported that unvaccinated individuals were more than five times more likely to get COVID-19, 7.5 times more likely to be hospitalized, and 14.5 times more likely to die from the coronavirus than people who had been vaccinated and boosted. Over the past nine months, approximately 234,000 people in the U.S. alone died who would have survived if they’d been vaccinated.

Vaccination and deaths from coronavirus

Hospitalizations and deaths among the vaccinated have started rising, but note that almost all of them occur in the elderly. Vaccination still provides substantial protection.

More data is needed, but one study suggested, interestingly enough, that vaccination does not seem to protect against long COVID. We’ll know more about the effects of BA.5 on hospitalizations and deaths over the next couple of months.

The Coronavirus Booster Poll

If you’ve had one or more coronavirus boosters, please tell us how it went.

 

Reinfections Make Things Worse

A recent sobering preprint study found that instead of getting better at fighting off the virus, the body seems to get worse at it. The more times a person gets reinfected with the virus – the worse off they tend to be. Given how well the virus is adapting to evade the immune response, this outcome may not be surprising, but it is different. Reinfections were considered rare until the Omicron variant hit.

Most people who were infected with Omicron were infected with the BA.1 variant, but the BA strain has mutated so rapidly that these people have only “limited cross-immunity” to the BA.2, BA.2.12.1, BA.4, and BA.5 variants.

A large study that looked at hundreds of thousands of people found that death rates, cardiovascular complications, and adverse lung outcomes – doubled in people who were infected more than once, and the risk of being hospitalized tripled.

The rates of people experiencing fatigue, musculoskeletal, and gut problems jumped up dramatically. While the worst hit occurred early in the reinfection, some risks remained elevated six months later. Interestingly the three symptoms most associated with ME/CFS and long COVID – fatigue, gut, and musculoskeletal symptoms – were not significantly elevated after six months – suggesting that the risk of coming down with long COVID may not be elevated by a reinfection.

Long COVID

There is some good news about long COVID. A symptom app tracking study found that the early Omicron variants may produce about less 50-70% less Long COVID than the Delta variant did. BA.5, though, may be producing a more serious illness and producing more infections in the lungs. Time will tell.

Uncertain Future

Falling Behind – the Fall Vaccines

The new vaccines expected in the fall that were developed to address Omicron were directed against the BA.1 variant – which is long gone. A recent Nature paper that dug deep into the immune response against the Omicron variants concluded that Omicron variants are “continuously evolving under immune pressure” and pose “great challenge(s)” to the idea that a prior infection and/or vaccination will be able to produce herd immunity. The authors worried that the next crop of vaccines may not be able to “achieve broad-spectrum protection” against the new variants.

At the beginning of July, the FDA told vaccine manufacturers that they needed to produce a vaccine targeting the BA.4/BA.5 variants by fall. That puts the vaccine makers and the FDA in something of a time crunch. By the time Pfizer’s and Moderna’s BA.1 targeted boosters were approved, BA.1 had been supplanted by very different versions of the virus.

In order the get the new vaccines out by fall, the drug makers will have to start manufacturing the boosters en masse before they’ve been FDA-approved. Pfizer has said it can tweak its mRNA-based vaccine pretty quickly.

One report, though, stated that people who have been vaccinated or have been infected still carry enough of the neutralizing antibodies that protect them against severe disease and death. It’s the levels of the “lower neutralizing antibody levels” that fend off the virus that have dropped – thus we have more infections but not as much hospitalization or death.

New (Old) Vaccine in Town

A new vaccine – the Novavax vaccine – is coming to the U.S. Recently FDA-approved, the Novavax vaccine is a more traditional vaccine that directly injects the spike protein – plus an adjuvant that enhances the immune responses to the protein – into the blood. If you’ve had the Shingrix vaccine, it’s similar to that.

Manufacturing problems left the vaccine two years behind its predecessors. While it was very effective against earlier strains of the virus, it’s not clear how effective this long-delayed vaccine will be against the Omicron variants. (Novovax says its data shows that it will provide substantial protection and that a BA.5-oriented version of the vaccine should be available by fall.) As with the mRNA vaccines, very rare cases of myocarditis in young people were found.

With the U.S. dumping tens of millions of unused vaccines, it’s not clear that there’s much demand for Novavax, but it does provide a more traditional alternative to the mRNA (Pfizer, Moderna) and adenovirus (Johnson & Johnson) vaccines.

Eric J Topol

Eric Topol decried the “COVID Capitulation” he believes has occurred.

COVID Capitulation?

Eric Topol, in a May blog titled “The COVID Capitulation” – which was published prior to the emergence of BA4/5 – decried the lack of attention given to the add-on effects of the continuing spread of the coronavirus. He estimated that the real number of cases was probably at least 500,000 per day – far greater than any of the U.S. prior waves except Omicron.

Cases of long COVID, and substantial amounts of sickness, hospitalizations, and deaths were resulting, yet the pandemic was being treated as if it was largely over. With the U.S. seeing over 175,000 COVID deaths in 2022 already – 10x that expected from the seasonal flu – and with much better vaccines than for the seasonal flu available – Topol calls the high death levels “unacceptable”.

Forget Variant Chasing – Instead, Create the Coronavirus Vaccine to End all Coronavirus Vaccines

How long the vaccines can be expected to hold such a rapidly mutating and spreading virus at bay is unclear. The virus has changed so much and so quickly that a prior infection – even one as recent as a month ago – may not provide much benefit for those infected with BA.5.

Two critics of the fall BA4.4/BA. 5-based vaccines argue that they will probably provide minimal improvements, and that instead of spending increasingly scarce funds (given Congress’s unwillingness to devote more funding to COVID-19) on a massive nationwide rollout, funding should go to producing next-generation variant-proof or nasal vaccines.

The Gist

  • Variants of concern are coronavirus variants that: may be able to increase transmissibility, produce a more severe disease, are better at evading the antibody response, are not knocked down as well by treatments or vaccines, or are harder to detect.
  • Only one coronavirus lineage – the Omicron lineage of variants – is producing “variants of concern” right now. The Omicron variants hit the U.S. hard at the beginning of this year, producing high rates of infection, hospitalization, and death. 
  • Since then, though, the Omicron variants have continued to evolve with stunning speed, with each variant becoming more transmissible and “immune evasive” than the former. The new more contagious variants produced more infections but proportionately fewer deaths, possibly because they tended to infected cells in the upper respiratory tract but not the lungs. 
  • The latest subvariants – called BA.4/5 – resulted in an evolutionary leap for the virus. BA.5 is so different from the earlier variants that one researcher called for it to be classified as a new coronavirus. 
  • The BA.5 variant’s “fitness” (its ability to reproduce and evade the immune system) has been called “off the charts” stronger than the past variants. This variant is so different that some researchers worry that even a recent infection from an earlier Omicron variant may not provide much protective immunity. 
  • BA.5 first showed up in South Africa where it rapidly increased infections as well as hospitalization and deaths – but not to the extent that had been seen with some of the earlier waves. The variant then moved to Portugal where, despite high rates of vaccinations, it produced large numbers of hospitalizations. 
  • It took just a month or so for the BA.4/5 variants to become – just recently – the dominant coronavirus strain in the U.S.  One worry is that some early (but preliminary) data suggests these variants may be infecting cells in the lungs. We will see over the next month or so the impact it will have. 
  • The vaccines were designed to protect against a  different variant altogether and their effectiveness against hospitalization and death has waned by about 20%. (The waning, however, is concentrated in the elderly. In other age groups they remain highly effective.) Studies suggest that over 200,000 deaths in the U.S. could have been prevented by vaccination over the past 9 months.
  • Some evidence suggests that the vaccines and/or past infections continue to produce neutralizing antibodies that protect against the most severe consequences of the virus. Antibodies that quickly tamp down the virus, on the other hand, appear to be waning. 
  • In contrast to past coronavirus waves, reinfection has become common. Studies indicate that people who are infected with the virus more than once experience greater rates of hospitalizations, cardiovascular complications, etc.
  • Interestingly, rates of the symptoms associated with ME/CFS/FM such as fatigue, gut, and musculoskeletal symptoms, do not seem to be increased long-term in reinfected people. Another study suggests that the early Omicron variants produce about 50% less long COVID than the Delta variant. It’s unclear, though, how much long COVID the BA.4/5 variants will produce. 
  • The FDA has instructed the drug companies to produce vaccines directed against the BA.4/5 variants, but whether they will be able to do so in the time span allotted is unclear. “Variant-chasing”, though, has become increasingly untenable given the rapid evolution of the virus. Efforts to produce a coronavirus vaccine that protects against all coronaviruses and their possible variations are underway. 
  • Treatment effectiveness is also starting to wane as the new variants evolve further and further away from the earlier strains. 
  • Nobody knows if the BA.4/5 variants will produce a little, moderate or large bump up in hospitalizations and/or deaths over the coming months, but the extreme contagiousness of these variants is producing recommendations to mask up in any crowded areas – inside or out. If you can handle boosters – they are recommended as well. If you’ve been boosted, please participate in the Coronavirus Booster Side-Effects poll on this blog and tell us how you did. 
  • Unfortunately, the coronavirus is expected to keep mutating and rolling out variants for the next couple of years. Thankfully, no “variants of special concern” which are both more contagious and more deadly have shown up. The virus, however, will likely continue to get better and better at evading the immune response. 
Eric Topol agrees that “variant chasing” in such a rapidly evolving virus is ultimately a fool’s errand and that we should put more resources into producing vaccines that are essentially variant-proof against all B-coronaviruses.

Ten different research groups are reportedly trying to create the coronavirus vaccine to end all coronavirus vaccines, and three are in clinical trials. The Mosaic-8 vaccine, for instance, which uses 60 fragments from eight strains of coronaviruses to build the vaccine, has been shown to work well in animal trials. Phase I safety testing in humans is expected to begin next year. Meanwhile, results from a US Army-produced mega-vaccine phase II trial should be out soon.

Topol believes we should also be producing nasal vaccines that stop the chain of transmission in its tracks. (The coronavirus usually invades through the nasal passages.)

Those and better antiviral drugs are the key, Topol believes, but neither are receiving the priority, they should. The answer for Topol is an Operation Warp Speed-like initiative to produce variant proof as well as nasal vaccines – which should be able to stop transmission – to the fore.

Treatments Falling Behind as Well

As the virus mutates more and more, it’s also leaving some treatments in the dust. Topol is not big on the antiviral Paxlovid which he reported is “being increasingly recognized to have a liability of rebound with infectiousness in many people after the 5-day blister pack pill”. He also worries that we may see drug resistance – something that’s already been seen with remdesivir – crop up in the coming months. He noted that the rapidly evolving virus has “already blown through most of the monoclonal antibodies that were previously highly effective”.

Topol argues that “We urgently need more safe and effective medications, preferably pills, easily administered shots (subcutaneously, not intravenous or intramuscular), or inhalation treatments.”

Many promising treatments are in the pipeline, yet support for them has waned. It’s this lack of attention to the evolution of the virus, the lack of support for mask-wearing, for vaccinations, for the development of better vaccines, for better drugs that for Topol signifies “Covid capitulation.”

Uncertain Future

It’s clear that the Omicron variant has unleashed a swarm of unforeseen mutations. Topol believes that with millions of immunocompromised people providing the virus with a kind of feeding ground, the virus will continue to mutate and that we should prepare ourselves for the possibility of something worse than Omicron showing up over the next year.

Kristian Andersen, a viral evolution researcher at Scripps Research, agrees. Not knowing what the future variants will look like – but knowing they are coming – Andersen states “we can be certain that they’ll continue to be more and more capable of immune escape”.

While they haven’t produced more severe diseases yet, that could be just around the corner. With our immune protection against the virus waning, we could be back in the soup in the near future if the virus makes an evolutionary jump that increases its severity.

Topol ends by stating, “It’s frankly sickening to watch this virus continue to outrun us, knowing we are so damn capable of getting ahead of it.”

Action Plan

Topol says that there’s no doubt that a new coronavirus wave is coming. What we don’t know is how deep and long it will be. We do know that it’s getting harder and harder to evade this virus. Dr. Preeti Malani, an infectious disease physician from the University of Michigan, told Business Insider that “Those of us who’ve escaped for 2.5 years? It’s gonna be hard to escape this one”.

That’s been my experience. Over the past couple of months, four people in my immediate family – all of whom evaded the coronavirus for over two years – came down with it. They were probably infected with the early BA subvariants – and thus may now be susceptible to BA.5. All had been vaccinated and/or boosted and all emerged OK.

Here’s one ” BA.5 Action Plan” that has been proposed.

(1) Mask Up!

So much virus is around that the chances of being around someone who is shedding if you’re in a crowd are high – even if you’re outside. Dr. John Swartzberg from The University of California, Berkeley, recently told the San Francisco Chronicle: “The chances of being around someone outside or inside who is shedding virus is very high,” infectious disease expert.

Mask use is way, way down, but given the contagiousness of the BA.5 variant, its ability to evade the immune system, and the increase in hospitalizations it’s produced in a couple of countries, masking up again in public, avoiding crowded areas, etc. makes total sense – particularly for people with ME/CFS/FM.

(2) Consider Getting Boosted

Everyone can make their own decisions about boosters. I’ve been vaccinated and boosted twice and have done fine. Others have had real problems. If you’ve gotten through the vaccines or boosts OK, another booster now could help.

(3) Create a Get Paxlovid Quick Plan

If you’re high risk, have a plan for quickly getting access to Paxlovid. Paxlovid is apparently available for free across the US. The more quickly you take it, the better it works (also, you must start it within 5 days at the latest).

(4) Improve Indoor Air Quality

Maintain high levels of ventilation and air purity.

(5) Accept that We’re Going to be Dealing with COVID Variants for Several Years

BA.2.75 mutations

Mutations found in the BA.2.75 variant of the virus which recently emerged.

The SARS-CoV-2 virus is expected to keep evolving for several more years and has recently produced an entirely different variant of concern called BA.2.75 (aka Centaurus). We don’t know much about BA.2.75, but its boatload of mutations may take immune evasion several steps beyond even BA.5. Calling the number of mutations in BA.2.75 “remarkable”, one researcher suggested that the variant could herald in the next wave of infections after the BA.5 wave, that is. BA.2.75 emerged in India but has been found in the U.S., Canada, Europe, Japan, etc.

One person, frustrated by the seemingly continual emergence of new, highly transmissible virus types, asked: “Why is the solution space so big for this goddamn virus?”. It’s a great question that no one has the answer to yet. One thing is clear, though – we’re not nearly done with the coronavirus.

 

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