Since its discovery in November, the Omicron variant of SARS-CoV-2 (the virus that causes COVID-19) has continued to adapt and evolve at an extremely fast pace to evade the body's natural defence system. It likely won't be the last variant to do so. The next phase of the pandemic is set to bring a high risk of being reinfected with the virus, intensifying the race between the virus and our immunity against it.
The BA.4 and BA.5 lineages of the Omicron variant, which were behind South Africa's recently finished fifth wave, are now causing surges of infection in various countries around the world. These variant spinoffs are dramatically different from any of their predecessors, including the original version of Omicron. A further variant, BA.2.75 is already waiting in the wings, although it is not yet clear how well it will spread.
Infections come with risks
Having COVID-19, no matter how mild the case, comes with risks. That's because the virus can do damage to your body - even after your immune system kicks into gear. Even if you do not get seriously ill, you may end up still struggling with long-COVID many months later.
A May report from the US Centres for Disease Control found that one in five people between the ages of 18 and 64 had at least one persistent COVID-19 symptom a month after recovering. The report cautions that as more people get exposed to this virus, this risk could increase. Globally, the number of cases that result in long-COVID could be as high as 54%, according to a 2021 review in JAMA.
In highly simplified terms, there are two main aspects of immunity. The first line of defence comes from antibodies, which are produced by your B cells. These proteins are fighters that target the virus itself to stop it from entering your cells and in doing so stop you from getting infected. The second line of defence comes from killer T cells, which destroy any cells that have been infected with the virus. When successful, it is this second part that prevents a SARS-CoV-2 infection from turning into a serious case of COVID-19.
Understatement:
"The rapid emergence of new variants makes
variant-specific vaccine development dificult" https://t.co/kLAuVbkDps@NEJM today
a.k.a variant chasing
Pan-β-coronavirus and nasal vaccines would avoid V-chasing and can help get is to variant-proof status, ahead of 🦠 pic.twitter.com/fIsYc3bdlK
-- Eric Topol (@EricTopol) July 6, 2022
"The emphasis should be on avoiding infection simply because we still have many people who are not well protected," says Professor Wolfgang Preiser, head of medical virology at Stellenbosch University. "There's a lot we still don't know and there are worrying reports of breakthrough infections or reinfections still leading to long-COVID."
Those most vulnerable are people who are unvaccinated - which is around half of adults in South Africa - and people with weakened immune systems who are more likely to develop severe disease or have persistent COVID symptoms.
Focusing on quality, not quantity
"When the vaccines started rolling out and we saw all these robust antibody responses, we thought that we had vaccines that were going to be able to prevent infection from ever happening and that whole paradigm has completely been destroyed by the variants of concern," reflects Professor Penny Moore, South African Research Chair of Virus-Host Dynamics at the University of the Witwatersrand and the National Institute for Communicable Diseases.
But there are so many layers to immunity that it's hard for the virus to outsmart every mechanism in place. Antibodies are a more specific and immediate response to the virus, making it easier for mutations to concentrate on that aspect of the immune system. Newer variants like BA.4 and BA.5 are particularly adept at side-stepping this particular branch of immunity.
As the virus changes, so does your response, explains Moore. And when it comes to antibodies, she says that quality is much better than quantity.
"In very much the same way that we're used to seeing viruses changing and picking up mutations, antibodies do the same thing," Moore says. They also get better and better and the more exposures you have, the better your antibodies get at recognising the pathogen [SARS-CoV-2]."
By now, most people in South Africa have already been exposed to COVID and developed some protection against it. This didn't come at a light cost though. The exact toll of the pandemic is unknown, but likely over 250 000 people have died of COVID-19 in South Africa - the South African Medical Research Council estimates 325 000 excess natural deaths since May 2020, around 80% of which are thought to be COVID-19 deaths.
Race to Develop #Omicron -proof Boosters Before Northern Winter https://t.co/KVxoLXUVor
-- Spotlight (@SpotlightNSP) July 15, 2022
T cell defences still standing
Being vaccinated teaches your body to respond to the original version of SARS-CoV-2 that was circulating at the start of the pandemic. But later exposures to newer variants, like Omicron, can generate a different attack pattern from your cells, says Moore. That's why the next round of jabs is looking at catering toward a different form of the virus - to help broaden your immune response and increase the quality of the body's defence system.
The other thing to consider is that antibodies don't stick around for a long time. These attacking proteins wane after a few months, which then leaves you vulnerable to infections once again. "Reinfection has just become a part of our lives now," says Moore. "Antibodies are just one part of the immune system, and T cells do a really fantastic job, generally, at preventing severe disease. And that's what's changed. Our focus has now shifted away from preventing infection, which has become much harder to do, and is more focused on preventing disease and death."
T cells offer a much broader response that's harder to get around because they can recognise multiple parts of the virus. These cells, while harder to measure, are also more durable and do not wane in the same way as antibodies.
Professor Wendy Burgers, a virologist at the University of Cape Town, says, "The T cell response is now doing more of the heavy lifting. Before antibodies were still protecting from infection so that was the biggest pressure that the virus was feeling. The very first thing the virus needs to do is get into a cell and antibodies are there blocking its way so that is the first foe it must fight."
As the virus continues to evolve, there is a risk that it could also start getting around this part of the immune system -- particularly if antibodies become less of a challenge. Burgers says there is a possibility that future variants could change to interrupt the alerts to T cells telling them where to attack, but this is much harder to block completely.
An April paper in JAMA found that even though Omicron had changed its structure significantly and some mutations did help the variant hide from T cells, the overall response was unaffected. Since T cells recognise a wider section of the virus, these changes didn't lower the protection offered by vaccines against severe disease.
A mixture of immunity
Vaccines are kind of like a training arena for your immune system where your cells can prepare and warm up. Each jab works slightly differently and stimulates its own response, explains Dr Richard Lessells, an infectious disease specialist at the University of KwaZulu-Natal. That's why getting a mix of shots can help broaden your potential counterattacks.
"It is a little bit different with each vaccine," Lessells elaborates. "For example, the mRNA vaccines like Pfizer give you a high amount of antibodies but these decline quite quickly. Whereas Johnson & Johnson's option may not go as high but lasts slightly longer."
But with variants in the picture, immunity needs to broaden beyond just what these vaccines can offer us, says Lessells. Gaining the upper hand over the virus means preparing your body to attack different parts of the virus to withstand future changes to the germ's structure.
Ideally, to avoid the risk of health complications or developing severe disease, you wouldn't get infected at all. A June preprint found that even though your immune response gets better with each exposure to the virus, getting reinfected does carry a slightly increased risk for more serious health complications, like heart disease or kidney disorders.
Research shows that people who have been both vaccinated and infected with the virus have better immunity. This mix, called hybrid immunity, works well because vaccines offer a primer that rings alarm bells more broadly in your body while infection will target specific spots, like your nose and lungs, explains Burgers.
A June paper in the New England Journal of Medicine (NEJM) found that hybrid immunity offered the best defence against reinfection. The study found that people who had been infected with the Delta variant and received at least one dose of a vaccine were the least likely to be reinfected by the variant. A more recent NEJM article reported similar findings in the context of booster doses and more recent variants.
March data from Sweden shared in The Lancet showed that people who had been infected previously and received one dose of a vaccine were 58% less likely to get COVID a second time when compared to people who only had natural immunity. On top of that people who were vaccinated extended the protection against reinfection by an additional nine months.
"When you're exposed to these different variants, it's likely that it's broadening your immunity," explains Lessells. "That's not something you should be trying to achieve. It's not like you should go out to get infected multiple times so that you get this nice broad immune protection."
More targeted vaccines
"The holy grail of all vaccination is to prevent infection completely," says Professor Clive Gray, an immunologist at Stellenbosch University. "The problem is that very few vaccines do that."
It's especially hard to develop jabs that can do this when it comes to viruses like SARS-CoV-2 that target the respiratory tract, he notes. Around 15% of seasonal common colds are caused by different types of coronaviruses.
Influenza is another good example of this. Many people get sick during flu season and build up natural protection against the virus. But the germ is constantly adapting so what comes next year will be slightly different and you can get sick once again.
"We need to play catch up every season," remarks Preiser. "With the flu vaccine, we try to anticipate which few variants are going to cause the next seasonal outbreak. So, we're trying to guess and then produce the vaccine, all of which is not perfect. And this is why influenza keeps being a problem. Yet, influenza vaccination is a very good means of protecting the vulnerable against severe flu."
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A similar dynamic might now be developing with SARS-CoV-2.
"It's going to be an ongoing battle," Preiser cautions. "I don't think we are at a stage yet where we can sort of predict what's going to happen in future."
BA.4 or BA.5 vaccines
On 28 June, the US Food and Drug Administration met to discuss the design of future COVID vaccines. An advisory committee from the body recommended that the next jabs should be tailored to defend against the Omicron variant. This newly structured shot would serve as a booster to help head off impending waves from the next form of the virus. Exactly which variant will be used in this design hasn't yet been agreed upon, although the committee is strongly considering using BA.4 or BA.5 as the base.
Experts at the World Health Organization reached a similar conclusion on 17 June. The global health body noted that the next generation of vaccines should focus on creating "broader immunity against circulating and emerging variants while retaining protection against severe disease and death".
New vaccines have been developed in record time in response to the COVID-19 pandemic, but vaccine development and production still don't happen overnight. The variant has to be chosen then manufacturers must create and test the new jabs. The whole process means it will at best be months before such a booster shot is ready - and by then something completely new could be circulating.
"We're always playing catch up," Burgers says. "We don't know if by the time they have the vaccines ready, whether we'll be on to the next variant, or if it will just be another variation of Omicron. So, we are always behind."
An alternative approach is to develop a vaccine that addresses a broad spectrum of coronaviruses - otherwise known as a pan-coronavirus vaccine. Such a vaccine might not be limited to just SARS-CoV-2 and its known variants but might try to also tackle other coronaviruses like those that cause the common cold or the one that led to the 2003 SARS outbreak or some combination of all of the above.
Developing such a variant-proof vaccine is incredibly difficult to accomplish and likely won't be as quick to the finish line as the first batch of jabs. A handful of these more universal vaccines are being tested, including by companies with existing candidates in the field like Moderna and Pfizer. But a lot more research has to be done before we will know whether any of these pan-coronavirus vaccines are safe and effective.
