Almost a year ago today, in the middle of a freezing Melbourne winter, a young woman fell sick. The bug soon spread to her housemates. The three, who had already had COVID-19 a year before, probably thought they were sharing a nasty cold.
The young woman diligently lined up for a PCR test – this was in July 2021, when we still did that – and, to her surprise, discovered she had COVID. Again. Some 368 days after her first diagnosis.
Mask wearing is again being strongly encouraged.Credit:Getty
She and her housemates were Australia’s first documented cases of reinfection. Natural antibody levels generated in response to their first infections in 2020 had waned over 12 months to such a point they were vulnerable to the newly emerged Delta variant. It was such a novel thing at the time that their case made it into the scientific literature.
A year later, what was once novel is about to become de rigueur. The arrival of Omicron and its subvariants has seen vaccine effectiveness wane from the giddy mid-90s percentages of the first doses to around 40 per cent by some estimates. With that sharp drop will come increasing numbers of reinfections.
“Right now the vaccines we have will not stop the pandemic,” says Associate Professor Nathan Bartlett, head of viral immunology at the Hunter Medical Research Institute and University of Newcastle. “We can keep boosting and protect people from severe disease and death – but this will not stop infections.”
To understand what has happened to the pandemic, we need to start by looking at what has happened to the virus.
When a person with SARS-CoV-2 is infected, they can have up to 3 million viral particles inside their cells. Each replicates between three and seven times before the infection is cleared. On average, for every two people infected, you get one mutation. These random mutations are the raw material of evolution.
It’s not yet clear where Omicron has come from. It is so genetically distinct some scientists think it may have emerged from a person with a long-term chronic infection – or even from an animal. Or it may have come out of one of the many places on the Earth where genomic surveillance is patchy or non-existent.
Whatever the answer, it remains true that if you slow infections you slow mutations and handicap viral evolution. Globally, humanity has proven unable to do this, in part because less than two-thirds of the world’s population have received two doses of a coronavirus vaccine (just 27 per cent have received a booster).
“Until we address vaccine equity there is always going to be the potential for new variants to emerge and spread,” says Dr Megan Steain, a University of Sydney virologist working on a COVID-19 vaccine project.
The World Health Organisation is reporting a million confirmed new infections a day; an epidemiological model built by the US-based Institute for Health Metrics and Evaluation estimates the true number at north of 16.7 million.
These infections rev the engine of evolution higher and higher.
During the pandemic’s first year, as the virus spread around the globe, meaningful evolution was slow. But in the past 18 months, it has accelerated dramatically. A study published in Science in May estimates BA.2 is now nine times fitter than the virus that first emerged from Wuhan.
Viruses respond to the evolutionary pressures they are under. At the start of the pandemic, viruses that could move faster and infect more people, like D614G and Alpha, were king.
“The pressure is no longer infectiousness,” says Dr Denis Bauer, a CSIRO scientist building machine learning models to track new variants. “The current version of the virus is already much more infectious compared to the original Wuhan strain.”
Instead, with so many people having either natural or vaccine-generated immunity, COVID-19 is now under evolutionary pressure to find ways around antibody defences, in an arms race between the virus and our immune systems.
Delta had some ability to evade antibodies. Omicron and its subvariants – BA.2 through to BA.5, so far – take this to the next level.
In people given a booster dose, the level of neutralising antibodies – the key marker of vaccine protection – were six times lower against Omicron compared to the Wuhan strain, according to a letter published in the New England Journal of Medicine. Against BA.5 they were 21 times lower. Similar antibody drop-offs were seen in people who had a prior infection.
Rapid antigen tests are in high demand.Credit:Nine News
Translated into predicted vaccine effectiveness, the results do not make for good reading. Efficacy against symptomatic infection from Omicron likely falls to around 40 per cent six months after a booster, according to predictions by Steain’s team. The numbers for BA.5 are likely to be worse. Importantly, though, protection against serious illness continues to hold up at around 80 per cent, and can be kicked back up into the mid-90s with a booster jab.
And Omicron appears to be particularly difficult for the immune system to get a grip on. People infected with the new variant do not seem to get as strong an immune boost as from infections with prior variants.
“I don’t want to say Omicron was a worst-case scenario – but it wasn’t ideal,” says Professor James Triccas, a microbiologist at the University of Sydney and co-author of a recent study of immune responses. “We’re expecting it to hit us reasonably hard here in terms of case numbers.”
The next variant
Alpha and Delta may have lulled scientists into something of a false sense of security, says Triccas. The expectation was the virus would grow better at evading immunity, but only slowly.
“The early variants, Alpha and Delta, had a devastating global impact, yet the vaccines did still work against them. Everyone was expecting we’d get a continual emergence of Delta variants. Omicron came out of the left field.”
Indeed, the variant is so different to Delta that some scientists suspect the virus has jumped from humans into animals – and now mutated versions are spilling back into humans.
One thing appears certain: Omicron and its variants will not be the last. The virus is a long way from exploring all its possible mutations, says Bauer.
While high levels of infection continue around the world the virus will still have “ample opportunity to rapidly find cracks in our immunity”, says Bartlett. “There is no sign that this will end.”
Does that mean we should expect to continue to see more increasingly immune-evasive variants?
“Unfortunately, I think that’s going to be a yes,” says Steain. “If it’s facing rising levels of immunity, a good way to keep infecting people is to evade that immunity.”
It’s often said viruses evolve to become less dangerous. But this is not the case at all, says Bauer. Nature is far more complex than that: “There are no rules.”
Given the continued high rates of mutation, it is plausible a future variant could be both immune-resistant and more severe, says Bartlett. We’d be “forced to return to lockdowns and border closures – that we’re still recovering from”.
Whatever happened to herd immunity?
What does this mean for the pandemic? Can we expect to get reinfected continuously?
“Yep. I think that’s probably fair to say at this point,” says Steain. “Unless we’re able to design a vaccine that induces sterilising immunity. But I don’t know how achievable that is.”
SARS-CoV-2 typically gains entry to our bodies through our nose. To stop the virus infecting us altogether – known as sterilising immunity – we probably need antibodies right there on the front lines. Current vaccines are injected into the arm and raise high levels of antibodies in the blood, but not so many in the nose.
“Look at the viruses we’re able to control well with vaccination: they are the type when, if you get infected, that’s enough to control the virus through your life,” she says. “Vaccination just trains your immune system to do the same thing. Think about the flu – you repeatedly get infected despite having previous exposures.”
While our vaccines may still allow us to get infected and reinfected, they continue to do an excellent job at protecting us against serious illnesses.
In Steain and her colleagues’ study, protection against severe disease from Omicron is predicted to fall to about 80 per cent six months after a booster, before jumping back up to 98.2 per cent after boosting. Importantly, they also cut how long we shed the virus – another way of reducing the chances of a new variant emerging.
Antibodies aren’t the only weapons our immune systems have to protect us from COVID-19. T cells – virus hunter-killers – are slower to react than antibodies but pack a much more powerful wallop.
Some scientists suspect they may be playing a role in protecting us from serious illness. And they are less easily tricked by mutations to the virus.
“Unlike antibodies, which can be affected by small changes in the virus’ spike protein, the good thing about T cells is they can detect conserved regions within the spike,” says Dr Gabriela Khoury, a Monash University microbiologist studying how T cells respond to COVID vaccines. “You’ll still potentially develop a T cell response [to new variants].”
The long-touted solution to new variants is updated vaccines. Our current vaccines train our immune system using the version of the virus that first emerged from Wuhan; an Omicron-specific version should in theory encourage our immune systems to build new and better antibody defences.
Pfizer and Moderna both have updated vaccines in the final phases of clinical trials. Both companies have reported their new jabs work better against Omicron than current vaccines. Australian regulators have already given Pfizer’s new jab a provisional determination, the first step towards a quick listing.
But several new studies raise an intriguing wrinkle: a phenomenon known as immune imprinting. Or, more colourfully, original antigenic sin.
When Omicron first arrived, some scientists were hopeful this new, mild variant could give us all a useful immune boost without making us too sick. But a study in Science led by Imperial College London’s Rosemary Boyton found people who had been triple-vaccinated and infected early in the pandemic had worse immunity against Omicron compared to those who had been vaccinated but never infected. How can this be?
Our immune systems build a library of all viruses they have fought before, allowing them to quickly raise antibodies to any new invaders. If the virus changes substantially, those antibodies may no longer be as effective.
When the new invader comes along, we need our immune system to design new antibodies. But in some cases, our immune system can keep producing antibodies to the first virus it saw, not the variant – leading to reduced immunity. This may partially explain why frequent reinfections occur, Reynolds and her team write.
Other experts The Age spoke to were less concerned.
Original antigenic sin might slightly hobble our immune systems and vaccines, but with boosters, they still work well enough, says Associate Professor Menno van Zelm, head of Monash University’s Allergy and Clinical Immunology lab. And, theoretically, if new variants continue to mutate, eventually they will be so different that our immune systems will be able to spot them and make new antibodies.
“At the moment we know … we lose some effectiveness of the vaccine,” Van Zelm says. “But it still works very well. At this stage, I’m not too concerned – I’m mostly intrigued.”
A forever plague?
As SARS-CoV-2 grows increasingly capable of evading vaccines, reinfection rates are going to go up.
“Until we have a vaccine that blocks transmission, we’re going to see more waves of COVID-19, it’s not going away,” says the Garvan Institute’s Dr Deborah Burnett, part of a team designing a new vaccine.
Health departments in Victoria and NSW told The Age they are still working to compile reinfection figures. But in Britain, where such data is available, the risk of reinfection jumped 16 times higher between May 2021 and January 2022.
What is ahead for the pandemic, now Omicron and its cousins have arrived?Credit:AP Photo/Ted S. Warren
However, reinfections still make up a very small proportion of the total number of infections. New York State recorded 47,021 infections last week; just 16 per cent were reinfections.
That may change soon. More than half of Victorians have been infected with COVID-19. University of Melbourne epidemiologist Professor Tony Blakeley’s modelling is forecasting about six million new infections in the next 18 months. “Voila – a lot of the infections have to be reinfections,” he says.
In some rare cases, scientists have even found people who were reinfected with Omicron less than a month after being infected with Delta. In Australia, authorities have now lowered the period at which people need to watch for reinfections from 12 weeks to 28 days.
But this is not the norm. The average time between infection and reinfection in Britain remains about 10 months.
Still, the question now is how we break the cycle, says Bartlett.
One option being explored: vaccine boosters designed to be sprayed into the nose, which might generate those crucial frontline antibodies that could directly block infection.
Animal studies are promising, and at least three projects are in phase 3 trials (the final stage before approval). Some vaccine developers even imagine they could be available over the counter at pharmacists: a quick spray every few months to keep you safe.
Triccas heads another effort, backed by the international Coalition for Epidemic Preparedness Innovations, to build a vaccine with broad protective immunity against current and future variants.
Professor James Triccas in his lab at the University of Sydney.Credit:Nick Moir
The team are studying mutations from existing variants, as well as those seen in animal viruses that are close cousins of SARS-CoV-2, to understand where the virus might head next. They hope to build a vaccine with a single engineered spike protein that contains combinations of these different mutations, which would hopefully encourage the immune system to generate an extremely wide arsenal of antibodies. Human clinical trials are due to begin next year.
“The key thing to remember is the current vaccines are still very effective at reducing severe disease in most people,” says Burnett.
“Australia is experiencing a COVID wave. We need to manage it with the tools we have available now. Everyone who is over 50 should absolutely get their fourth booster. And everyone should be wearing masks in public settings. Because until we have a universal vaccine that blocks transmission, we need to work with the tools we have.”
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