New research shows the latest Omicron strains are more able to infect people who have been vaccinated, and multiple infections can cause future serious illness. By Rick Morton.

The next coronavirus variant is already here

A virologist at Sydney’s St Vincent’s Centre for Applied Medical Research.
A virologist at Sydney’s St Vincent’s Centre for Applied Medical Research.
Credit: Kate Geraghty / Nine

Overnight on Tuesday, as an independent medical advisory committee met in the United States to discuss a booster program for Covid-19, a new wave of infections was already taking hold.

In the week before the meeting of the Vaccines and Related Biological Products Advisory Committee to the Food and Drug Administration, early lineages of the Omicron variant were being pushed out by even quicker, “relatively troubling” cousins: BA.4 and BA.5. These two sublineages made up 33 per cent of all cases in the US for the week of June 18. A week later, they accounted for more than half. The data was updated while the FDA committee was still discussing its options for vaccines.

“I would like to conclude the meeting by saying that I think we have done the best we can in a difficult situation with imperfect data and inability to say what is going to follow what looks like an Omicron 4/5 wave,” the committee’s acting chair, Dr Arnold Monto, told the meeting.

“We’ve looked at the options that are available and come up with a recommendation and some advice that FDA can follow as we move forward into uncharted territory. Unfortunately, looking in the past does not help us a great deal to look in the future for this virus which has baffled a lot of us and made predictions almost irrelevant.”

Monto was almost comically pessimistic in his closing remarks, but the public health professor’s mood tapped into a growing fatigue in the medical community and among researchers. The SARS-CoV-2 pathogen continues to produce mutant strains, each one gifted with a set of properties that make it more efficient or more dangerous or both.

Take Omicron, for example, which was discovered in November last year. Its original BA.1 strain is no longer circulating, replaced by BA2.12.1. Now, BA.4 and BA.5 have arrived. All in the space of seven months. World Health Organization analysis, based on early studies, shows that these new strains have a “growth advantage” over early Omicron types and are even more capable of evading immune responses.

“The rise in prevalence of BA.4 and BA.5 has coincided with a rise in cases in several WHO regions,” the organisation said in its weekly epidemiological report. “In some countries, the rise in cases has also led to a surge in hospitalisations and ICU admissions; however, the current evidence available does not indicate a change in severity associated with any of the three Omicron descendent lineages BA.2.12.1, BA.4 and BA.5.”

Nevertheless, the concern expressed by Dr Bruce Gellin at the American advisory committee meeting on June 28 is that humanity has been, and still is, one step behind the virus.

“Without a plan, we’re going to be playing Whac-A-Mole as this virus evolves, because it is going to continue to evolve,” he said.

“We will get better at this, but we still need to get ahead of it. The vaccines we have are miraculous, but they are first-generation vaccines, and we are going to need to have vaccines that are more durable, have broader protection and decrease transmission.”

Despite these sobering updates, there is also good news. On June 23, researchers from the Imperial College London, led by Dr Oliver Watson, published data that suggests the global vaccination program saved almost 20 million lives in its first year. The paper, published online in The Lancet Infectious Diseases, notes that most but not all of this figure is due to “direct protection” of people who were vaccinated.

“Using our model fit to excess mortality, we estimated that most deaths averted were due to the high levels of individual-level direct protection conferred by vaccination, with 79 per cent (15.5 million) of deaths averted through direct protection,” the paper says.

“Vaccine impact was also conferred through reducing the levels of burden placed on healthcare systems, reducing the number of days that healthcare capacity would have been exceeded and therefore contributing to an overall lower fatality rate from infection.”

Globally, there have now been 540 million confirmed cases of Covid-19, with 6.3 million reported deaths. In other words, without vaccines, the fatality caseload would be more than four times higher.

While US officials discuss whether an Omicron-specific booster, or one even more targeted to the BA.4 and BA.5 subvariants, can or should be rushed to the public ahead of the northern hemisphere winter, Australia is experiencing its new wave right now.

Queensland’s chief health officer Dr John Gerrard told the ABC on Tuesday that 38 per cent of genome sequences for the SARS-CoV-2 virus in the state are of the newest, more efficient subvariants.

“We are now in another established wave of Covid-19 due to the BA.4 and BA.5 subvariants,” he said. “There’ll be a stress on the hospitals in the next few weeks as more and more people get admitted.”

Similarly, in New South Wales and Victoria, authorities have warned that the new variants are circulating in communities and growing rapidly. On June 23, the NSW Department of Health noted: “This is likely to result in an increase in infections, including in people who have previously had Covid-19.”

The study relied upon by NSW in making that comment, a preprint that has yet to be peer-reviewed, is also cited by the WHO. Study authors from Peking University in China, led by Yunlong Cao, report that several mutations in BA.4 and BA.5 “enable stronger immune evasion”. Essentially, they are more able to infect people who have been vaccinated.

Most “strikingly”, the authors say, these new variants even appear to evade neutralising antibodies from prior Covid-19 infections.

“Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants,” the study says.

“Unlike when Omicron first appeared, now Omicron sublineages could target the humoral immunity induced by Omicron itself, such as post-vaccination Omicron infection.”

In this study, researchers noted another troubling and curious development: survivors of the first SARS virus in 2002 who had been vaccinated for Covid-19 had plasma that looks entirely different from that of the general population who had received the same vaccine. This is crucial because it allows “a striking neutralisation loss” caused by subvariants such as Omicron BA.4 and BA.5.

That these are more potent suggests there are “certain mutations” in these strains that avoid the broad neutralising antibodies found in sarbecoviruses, the subgenus of pathogens that includes both SARS and SARS-CoV-2. If scientists were planning on using these broad sarbecovirus antibodies as a way to hedge vaccine formulations, then this study suggests they will not have much luck. BA.4 and BA.5 have essentially “met” the first SARS virus from 2002-2003 and found the defences produced by the human body in its wake even easier to override.

Similarly, because breakthrough Omicron infections mainly “recall” immune memories from the original “wildtype” Covid-19 virus, this reduces the diversity of antibodies and “may further facilitate the appearance of future mutants”.

The paper notes that this poses “a great challenge to the currently established herd immunity” achieved through vaccinations.

“Similarly, these also suggest that Omicron BA.1-based vaccine may not be the ideal antigen for inducing broad-spectrum protection against emerging Omicron sublineages.”

Time is of the essence. More than two-and-a-half years into the pandemic, with at least half a billion infections, there is some early evidence that reinfection is not only possible but even worse for long-term health.

A June 17 preprint paper by Ziyad Al-Aly from the Washington University School of Medicine looked at more than 250,000 Department of Veterans’ Affairs clients who were infected with Covid-19 – 39,000 of whom were reinfected with the virus – against a control group of 5.4 million people to determine the risks of becoming sick with SARS-CoV-2 more than once. The results were worrying. The study found that repeat infections made it more likely that a person would experience, be hospitalised for or die from other conditions and causes down the track.

“We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalisation, and adverse health outcomes in the pulmonary and several extra-pulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders),” the paper says.

“The risks were evident in those who were unvaccinated, had one shot, or two or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection.

“Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections.”

University of Cambridge postdoctoral researcher Ben Krishna wrote in The Conversation that while this isn’t “good news”, the results “need to be interpreted carefully” because the study population had a median age of 60, one-fifth of them smoked and 80 per cent were unvaccinated.

“It suggests that reinfections increase your general risk of health problems. But it’s worth remembering that the study population was at higher risk already,” he writes.

“Respiratory infections such as influenza are a leading cause of death globally, so it’s not entirely surprising that any extra respiratory infections will increase a person’s risk of health problems. This finding, however, is not the same as symptoms of reinfections being more severe.”

If symptoms are worse on reinfection, it is most likely because of waning immunity or significant changes in the virus genome.

There is a problem with the calculus involved in the race to study the SARS-CoV-2 virus: our understanding may or may not be rendered obsolete by subsequent mutations.

Researchers are still trying to find the molecular basis for Covid-19’s ability to attack the central nervous system (CNS), for example, and on June 13 Australian academics posted a preprint paper that proposed this mechanism may be similar to one implicated in Alzheimer’s disease. The scientists, led by Swinburne University’s Dr Mirren Charnley, targeted proteins in the virus that can build themselves into amyloid assemblies, which are known to have toxic effects on neuronal cells in the human brain.

“The cytotoxicity and protease-resistant structure of these assemblies may result in their persistent presence in the CNS of patients post-infection that could partially explain the lasting neurological symptoms of COVID-19, especially those that are novel in relation to other post-viral syndromes such as that following the original SARS-CoV-1,” the paper, published in Nature Communications, says.

Infectious diseases physician and UNSW Sydney Kirby Institute epidemiologist Professor Greg Dore noted that some interpretations of this paper are “alarmist” and that “human studies have shown limited brain infection or amyloid deposits”. Dore is a proponent of doing more research into the causes and outcomes of so-called long Covid and is a co-author on a June 7 preprint paper regarding a longitudinal study conducted by researchers attached to St Vincent’s Centre for Applied Medical Research in Sydney.

In one of the most rigorous studies to date, the authors, led by Associate Professor Lucette Cysique, followed 128 patients with mild or moderate Covid-19 infection at two, four and 12 months after diagnosis. What they found were small but persistent declines in cognitive function that resemble the “brain fog” reported by sufferers and “now recognised as a long-term consequence” of Covid-19 infection.

“This finding suggests that an ongoing pathological process affects all patients, and at least partially independently of pre-Covid-19 cognitive functioning,” the paper says.

“This also means that most impaired patients at the two-month visit performed in the impaired range across the study time line representing persistent CI [cognitive impairment]. This contrasts against studies which have focused on severe cases of acute Covid-19 where pre-morbid neurological conditions predict cognitive deterioration.

“Our finding of cognitive decline/failure to improve is in accordance with emerging cognitive and brain imaging studies assessing post-acute mild to moderate Covid-19 patients at 12 months post diagnosis.”

The authors note that only time and further study will determine if patients improve or recover after one year.

“This will be particularly important in older participants with acute mild disease entering the dementia age range who, according to a large Chinese study, are at risk of early onset cognitive decline,” the report says.

A potential “biomarker” target for therapeutic intervention has been discovered by this work, however, as the researchers found kynurenine pathway metabolites were linked to cognitive decline in the patient cohort.

Meanwhile, a constellation of well-documented or emerging potential outcomes of Covid-19 infection continue to be studied. One of these observed in two studies is “pathological” loss of bone density, especially in the long bones and the spinal column.

What remains unclear is whether these identified symptoms and outcomes can be dramatically revised or eliminated altogether with vaccination or therapeutic treatments. Even these are losing at least some of their shine.

In April, the US Food and Drug Administration revoked its authorisation for the lab-produced antibody sotrovimab because it was no longer effective against next-generation Omicron variants. Australia purchased at least 31,000 doses of sotrovimab late last year. In March, University of Sydney researchers led by Dr Rebecca Rockett showed that the drug’s use caused treatment-resistant mutations in the SARS-CoV-2 virus. The Australian regulator, the Therapeutic Goods Administration, is currently considering an application from GSK (formerly GlaxoSmithKline) to double the approved treatment dose to 1000 milligrams.

Finally, on June 22, another preprint paper examining 13,600 patients who contracted Covid-19 this year and were treated with oral antivirals Paxlovid and molnupiravir found another troubling trend: rebound infections. The study shows that 30 days after treatment, 5.4 per cent of Paxlovid recipients were still testing positive for the disease and slightly more were showing symptoms. Rates were higher for those treated with molnupiravir: 8.59 and 8.21 per cent for these rebound conditions.

“The rebound rates increased as the time elapsed after treatment, suggesting inadequate viral clearance by the treatments,” the paper says.

On Wednesday, 19 of the 21 members of the FDA advisory committee voted to include an Omicron-specific component in Covid-19 boosters used in the United States. The TGA in Australia will likely follow suit. It will take months to produce.

After the vote, Dr Bruce Gellin asked if there was a “Warp Speed 2.0” project “brewing somewhere”, referring to the 2020 US government effort to produce a Covid-19 vaccine that led to the Moderna product.

“We haven’t heard about that if there is,” he lamented. “Maybe in our next session we’ll get to hear what the plans are to get ahead of this, rather than chasing it.”

This article was first published in the print edition of The Saturday Paper on July 2, 2022 as "The next coronavirus variant is already here".

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