Mutants challenge COVID-19 vaccines

The much hyped vaccine strategy seems to be unraveling quickly as SARS-CoV-2 mutates faster than expected

Mutants challenge COVID-19  vaccines

When South Africa halted its keenly awaited roll-out of the Oxford/AstraZeneca vaccine in early February, the reverberations were felt across the world. The move dismayed not just the scientific community, but also the world community which was eyeing vaccines as its long-awaited ‘exit strategy’ from a year of pandemic chaos and disorder. For scientists, the real cause of worry was the reason cited for the cancellation: the vaccine demonstrated only minimal efficacy against the particular SARS-CoV-2 variant prevalent in the African country.

The Oxford-AstraZeneca adenoviral vector vaccine is one among the three promising vaccines authorised for emergency use by the world’s leading regulators as well as WHO. However, when the researchers at the University of Witwatersrand, Johannesburg, along with those from Oxford University, tested it on 2,000 volunteers in a phase I/II trial, they found that the shot’s efficacy against the mild and moderate COVID-19 illnesses caused by the predominant B.1.351 variant was 21.9%.

This was well below the 50% minimum threshold required for regulatory approval. At the same time, there was evidence that the vaccine was able to prevent severe disease and death among the volunteers.

With over 95 percent of the reported incidences, the B.1.351 variant was the dominant strain of SARS-CoV-2 in South Africa, a country that has recorded almost 1.5 million coronavirus cases and more than 46,000 deaths since the pandemic began, more than any other in Africa.

To make matters worse, the lethal B.1.351 variant had leaked into neighbouring countries and was on its way to all corners of the globe.

Hailed as the ‘Vaccine of the World’ owing to its affordable cost and ease of handling, the Oxford-AstraZeneca vaccine was considered a ray of hope for developing countries that lacked the refrigerated logistical facilities required by mRNA vaccines.

Hence, a repeat of the South African story could prove disastrous for poor nations, who can ill-afford costlier vaccines to mass immunise their populations.

Stealthy variants

As more and more SARS-CoV-2 variants are being reported in several regions of the world, scientists and drugmakers are racing to understand how far mutants like B.1.351 can impact the effectiveness of current vaccines.

It was in early December that South Africa alerted the World Health Organisation that it had identified a new variant that seemed to have mutations that might make the virus less susceptible to vaccines.

Known as B.1.351 or the 501.V2 lineage, the mutant spread so rapidly that it became predominant in the South African population in just a few weeks.

The variant has an unusually large number of mutations, including three in the receptor-binding domain (RBD) in the spike glycoprotein, that make the virus more lethal as they help the pathogen attach more easily to human cells.

South African researchers and the government say that the new variant is around 50% more contagious and it may be behind the second wave of the COVID-19 pandemic in the country.

Another mutation, the E484K amino acid modification, was reported to be “associated with escape from neutralising antibodies” which could adversely affect the efficacy of spike protein-dependent COVID-19 vaccines.

Adding to the misery, studies suggest that those who had previously been exposed to the original, or ‘ancestral’ strain, had no natural protection against the new strain.

So far, around 50 countries have already reported the presence of the South African variant.

B.1.1.7, another variant of concern, was first identified in September in southern England. It has since become the dominant strain in the UK and has spread to over 100 countries. The biggest danger of the British variant is its high propensity to spread. Recent estimates show that the variant is being transmitted 35 to 45 percent more easily than other variants and could be the dominant source of infection in the United States by March.

Finally, the P1 variant found in Brazil shares many of the mutations seen in the South African form even though genetic evidence suggests that it evolved independently. For now, data on this mutated version is hard to come by.

Even as laboratory studies suggest the possibility of “immune escape” with at least one of these variants, experts also warn that the actual number of variants out in the world could be far more.

Making an exact assessment of these SARS-CoV-2 variants is a challenge as few countries have invested in the kind of genetic surveillance needed to detect new variants.

Britain, which leads the world in surveillance efforts, has recently said that there are at least 4,000 variants of the virus that causes COVID-19. Britain sequences about 10 percent of its virus samples, whereas the United States has analyzed less than 1 percent of its samples, according to the US Centers for Disease Control and Prevention.

Vaccines crumble as viruses advance

Even as the much-touted Oxford-AstraZeneca vaccine stumbles, preliminary data suggests that at least four-fifths of the currently available vaccines with proven efficacy against the original virus may find it difficult to keep up with the rapidly evolving SARS-CoV-2.

Even though the mRNA-based vaccine from Pfizer Inc and BioNTech SE has been found effective against the B.1.1.7 variant found in the UK, new data released by the firms in February indicate that the levels of neutralising antibodies generated by the vaccine against the South African variant is about two thirds lower than what is seen in case of the original virus.

Even so, the antibodies “remain above levels that are expected to be protective,” the company said. The data is yet to be peer-reviewed.

The Pfizer results are part of tests against a lab-created virus that had all the mutations found in the South African variant, which is also thought to spread faster than the earlier version.

Pfizer and BioNTech said in a statement that there’s no real-world evidence that the South African variant can elude their shot.

Moderna’s vaccine, also authorised in many parts of the world, too fell short in its efficacy agaInst the SA variant, data shows. A significant reduction in coronavirus-fighting antibodies was observed in a study conducted by researchers from the US National Institute of Allergy and Infectious Diseases and Moderna Inc. Neutralising antibodies were found to be lower by a factor of 6.4 compared with those generated against the unmutated virus when the full group of South African mutations was examined in the lab.

Moderna said their vaccine was just as effective against the variant identified in Britain as against the original virus in people who had received two doses of the vaccine.

However, preliminary data from even highly anticipated vaccines under review in the US, EU and UK too don’t look promising against the fiendish South African variant.

The single-dose vaccine from Johnson & Johnson was demonstrated to be less effective at preventing infections in South Africa than elsewhere, even though it prevented hospitalisations and deaths in a large study. The vaccine’s efficacy rate dropped from 72 percent in the United States to 57 percent in South Africa. Obviously, the findings come with a significant cautionary note.

The case is not altogether different for the vaccine developed by Novavax Inc. The Maryland-based firm reported that its experimental protein-based vaccine was more than 85% effective against the COVID-19 variant identified in the UK. But the efficacy dropped to less than 50% against the lineage called 501Y.V2, detected in South Africa. The South African trial enrolled more than 4,400 participants and the UK trial recruited around 15,000.

The results increase the possibility that 501Y.V2 and similar variants will cause a significant drop in the effectiveness of other vaccines as well, experts warn.

No documented evidence is available on the efficacy of Sputnik V — developed by the Gamaleya Research Institute of Epidemiology and Microbiology, Russia — against the SA variant, and for SinoVac’s CoronaVac and Sinopharm’s vaccines, which are authorised to use in China and elsewhere.

Similarly, India’s Covaxin has no efficacy data against the mutants first found in South Africa and Brazil. Bharat Biotech said in late January that Covaxin was found to be effective against the UK variant. The study, however, is yet to be published.

According to some experts, Covaxin could work better against the new mutants because it generates protection against the whole virus, unlike the Covishield vaccine which is targeted only at its spike proteins.

Both these vaccines claim some efficacy against the UK variant, as it has only one mutation that matters. However, in the South African and Brazilian variants, there are many more mutations and hence a significant decrease in the efficacy may be seen.

Vax makers rev up shots

Meanwhile, vaccine makers are increasing efforts to make their shots effective against any variant.

Almost all the vaccine-makers say that they have begun updating their vaccines to tackle the new variants.

AstraZeneca, whose chimp virus vector vaccine has been found to have the lowest efficacy on the new variants, is planning to bring out a version that can protect against the variant from South Africa by the end of this year.

Moderna said the company has already started working on a new form of its vaccine that could be used as a booster shot against the variant in South Africa. “We’re doing it today to be ahead of the curve, should we need to,” Dr Tal Zaks, Moderna’s chief medical officer, said recently.

Moderna is also examining whether giving patients a third shot of its original vaccine as a booster could help fight emerging forms of the virus. The US biotech firm said it could produce a new vaccine ‘a little faster’ than the 42 days it took to make the original vaccine.

BioNTech too could develop a modified version of its vaccine against the variant in about six weeks, the company had claimed.

The mRNA technology used in both Pfizer-BioNTech and Moderna vaccines is versatile. This allows them to reformulate their vaccines much faster than those made using more traditional methods.

Johnson & Johnson, meanwhile, is tailoring a version of its vaccine using a protein patterned after the B.1.351 variant. It could potentially deploy it in countries where that version of the virus was a threat, the company said.

Novavax, whose protein-based vaccine demonstrated a high level of efficacy against the original as well as the UK variants, is currently working on a bivalent version that could effectively tackle the SA variant, the company said. (See related report).

Meanwhile, another key player on the scene, BioNTech, is talking to regulators around the world about what types of clinical trials and safety reviews would be required to authorize a new version of its vaccine that would be better able to counter the South African variant, Dr Ugur Sahin, the chief executive said in a recent interview.

Experts said that once-successfully developed, these vaccines would be cleared fairly early by regulators as the modified version of a shot may not require as extensive a review as the original one.

Eventually, booster shots will be required till the population achieves herd immunity.

Makers of virus neutralising antibody therapies are also drawing up strategies to try cocktails of multiple antibodies to deal with emerging variants.

“It is no surprise that the virus continues to mutate. This validates our decision to take a ‘cocktail’ or combination approach from the beginning, since this means the virus would need to mutate in multiple distinct locations to evade neutralisation by both antibodies,” said Alexandra Bowie, spokesperson of Regeneron Pharmaceuticals, Inc. The New York-based company was the first to secure an Emergency Use Authorization (EUA) from the US FDA for its antibody cocktail casirivimab and imdevimab REGEN-COV2 therapy last November.

Casirivimab and imdevimab are administered together for the treatment of mild to moderate COVID-19 in adults as well as in paediatric patients at least 12 years of age.

With two complementary antibodies in one therapeutic, even if one has reduced potency, the risk of the cocktail losing efficacy is significantly diminished, Alexandra explained.

According to her, in vitro studies confirm that both the antibodies continue to retain their potent neutralising capability against the B.1.1.7 as well as B.1.351 variants.

Even though casirivimab’s potency was found reduced against B.1.351 variant, it was still comparable to the potency that other single antibodies in development have against the original virus.

The variant first identified in Brazil (1.1.248) and recently seen in a patient in the US contains the same RBD mutations as the B.1.351 variant. Therefore REGEN-COV is expected to remain similarly potent.

Regeneron is preparing for any eventuality in case REGEN-COV does lose potency against a new strain as the virus continues to evolve. “Thanks to our VelocImmune antibody platform, we have a large pool of already available, virus-neutralising antibody candidates, and we are evaluating how these may form new combinations against future variants,” added Alexandra.

A speedy evolution?

The rapid emergence of new SARS-CoV-2 variants undercut the notion that vaccines alone will stop the pandemic anytime soon. Vaccines are not a silver bullet, say experts. The virus will mutate and change.

The evolution of SARS-CoV-2, though inconvenient, is not unexpected. Scientists had warned that SARS-CoV-2 might acquire new mutations that could potentially thwart vaccines, though few expected the prediction to come true so soon.

Many researchers attribute the speedier evolution of the virus into more lethal forms partly to the sheer ubiquity of the pathogen. Already, over 100 million people have been infected with the virus worldwide since the pandemic began. The more the number of people infected, the higher the chances of the pathogen mutating.

Immunologists warn against adopting a pessimistic attitude based on the data indicating declining efficacy. A fall in neutralising ability, they point out, does indeed mean the vaccines are less effective against the new variants, but neutralising antibodies are just one component of the body’s immune defense.

Hence, as long as the authorized vaccines continue to work, the highest priority should be to inoculate as many people as possible and to prevent the coronavirus from evolving into more impervious forms, experts say.

On the flip side, there exist many countries where no one has been immunised. Richer countries have been buying up doses and hoarding double or even triple the number of doses required to immunise their populations, anticipating future emergencies. In such a scenario, some populations may have to wait till 2022 at the earliest to gain access to any vaccines.

In countries like Mozambique, Zimbabwe and Zambia in the African continent, where the variant found in South Africa has reportedly been driving a surge in infections, the authorities have virtually no clue about when vaccines will arrive.

For the whole of Africa, only 20 to 35 percent of the population is expected to be vaccinated this year.

In addition, going by the current pace of production, reports show there will not be enough vaccines for truly global coverage until 2023.

In such a scenario, the virus would continue to spread, say experts. This would in turn allow more mutations to take place, which would make existing vaccines less effective. This will ultimately leave even inoculated populations vulnerable. In other words, no one is safe until everyone is.

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