Tweaked COVID vaccines in testing aim to fend off variants

Tweaked COVID vaccines in testing aim to fend off variants

Dozens of Americans are rolling up their sleeves for a third dose of COVID-19 vaccine—this time, shots tweaked to guard against a worrisome mutated version of the virus.

Make no mistake: The vaccines currently being rolled out across the U.S. offer strong protection. But new studies of experimental updates to the Moderna and Pfizer vaccines mark a critical first step toward an alternative if the virus eventually outsmarts today’s shots.

“We need to be ahead of the virus,” said Dr. Nadine Rouphael of Emory University, who is helping to lead a study of Moderna’s tweaked candidate. “We know what it’s like when we’re behind.”

It’s not clear if or when protection would wane enough to require an update but, “realistically we want to turn COVID into a sniffle,” she added.

Viruses constantly evolve, and the world is in a race to vaccinate millions and tamp down the coronavirus before even more mutants emerge. More than 119 million Americans have had at least one vaccine dose, and 22% of the population is fully vaccinated, according to the Centers for Disease Control and Prevention. Much of the rest of the world is far behind that pace.

Already an easier-to-spread version found in Britain just months ago has become the most common variant now circulating in the United States, one that’s fortunately vaccine-preventable.

But globally, there’s concern that first-generation vaccines may offer less protection against a different variant that first emerged in South Africa. All the major vaccine makers are tweaking their recipes in case an update against that so-called B.1.351 virus is needed. Now experimental doses from Moderna and Pfizer are being put to the test.

In suburban Atlanta, Emory asked people who received Moderna’s original vaccine a year ago in a first-stage study to also help test the updated shot. Volunteer Cole Smith said returning wasn’t a tough decision.

“The earlier one, it was a great success and, you know, millions of people are getting vaccinated now,” Smith told The Associated Press. “If we’re helping people with the old one, why not volunteer and help people with the new one?”

The study, funded by the National Institutes of Health, isn’t just testing Moderna’s experimental variant vaccine as a third-shot immune booster. Researchers at Emory and three other medical centers also are enrolling volunteers who haven’t yet received any kind of COVID-19 vaccination.

They want to know: Could people be vaccinated just with two doses of the variant vaccine and not the original? Or one dose of each kind? Or even get the original and the variant dose combined into the same injection?

Separately, the Food and Drug Administration has given Pfizer and its German partner BioNTech permission to start similar testing of their own tweaked vaccine. The companies called it part of a proactive strategy to enable rapid deployment of updated vaccines if they’re ever needed.

The Moderna and Pfizer vaccines, like the majority of COVID-19 vaccines being used around the world, train the body to recognize the spike protein that is the outer coating of the coronavirus. Those spikes are how the virus latches onto human cells.

Mutations occur whenever any virus makes copies of itself. Usually those mistakes make no difference. But if a lot of changes pile up in the spike protein—or those changes are in especially key locations—the mutant might escape an immune system primed to watch for an intruder that looks a bit different.

The good news: It’s fairly easy to update the Moderna and Pfizer vaccines. They’re made with a piece of genetic code called messenger RNA that tells the body how to make some harmless spike copies that in turn train immune cells. The companies simply swapped out the original vaccine’s genetic code with mRNA for the mutated spike protein—this time, the one from South Africa.

Studies getting underway this month include a few hundred people, very different than the massive testing needed to prove the original shots work. Scientists must make sure the mRNA substitution doesn’t trigger different side effects.

On the protection side, they’re closely measuring if the updated vaccine prompts the immune system to produce antibodies—which fend off infection—as robustly as the original shots do. Importantly, lab tests also can show if those antibodies recognize not just the variant from South Africa but other, more common virus versions, too.

Some good news: Antibodies aren’t the only defense. NIH researchers recently looked at another arm of the immune system, T cells that fight back after infection sets in. Lab tests showed T cells in the blood of people who recovered from COVID-19 long before worrisome variants appeared nonetheless recognized mutations from the South African version. Vaccines trigger T cell production, too, and may be key to preventing the worst outcomes.

Still, no vaccine is 100% effective—even without the mutation threat, occasionally the fully vaccinated will get COVID-19. So how would authorities know an update is needed? A red flag would be a jump in hospitalizations—not just positive tests—among vaccinated people who harbor a new mutant.

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Evidence for reduced antibody protection against SARS-CoV-2 variants

Evidence for reduced antibody protection against SARS-CoV-2 variants

Testing and vaccination—these are the pillars on which humanity is trying to get a grip on the Coronavirus pandemic. Although it is taking longer than many had expected, it is believed that it is only a matter of time before we are all vaccinated and thus protected. However, time is also working for the virus, which has now mutated several times, with variants B.1.1.7 from the United Kingdom, B.1.351 from South Africa and P.1 from Brazil spreading rapidly. These viruses have mutations in the so-called spike protein, the structure on the surface of the virus that is responsible for attachment to host cells. At the same time, the spike protein is also the major target of the immune response. Antibodies generated in response to SARS-CoV-2 infection or vaccination bind to the spike protein, thereby blocking the virus. A team led by Markus Hoffmann and Stefan Pöhlmann of the German Primate Center—Leibniz Institute for Primate Research and Jan Münch of the Ulm University Medical Centre has found that the SARS-CoV-2 variants B.1.351 and P.1 are no longer inhibited by an antibody used for COVID-19 therapy. In addition, these variants are less efficiently inhibited by antibodies from recovered patients and vaccinated individuals. Thus, convalescence from COVID-19 as well as vaccination may offer only incomplete protection against these mutant viruses. The study is published in Cell.

SARS-CoV-2 viruses invade lung cells in order to multiply. For the virus to enter a cell, it must first attach to the cell surface. For this, the virus uses its so-called spike protein, which is located on the viral envelope. The spike protein is also the target for therapies and vaccines aimed at preventing the virus from replicating in the body.

At the beginning of the pandemic, SARS-CoV-2 was relatively stable, but recently several viral variants have been detected and are spreading rapidly. Variants B.1.1.7, B.1.351, and P.1, which first appeared in the United Kingdom, South Africa, and Brazil, respectively, have mutations in the spike protein and some are located in areas targeted by currently used antiviral agents and vaccines. “This is worrisome because the rapid spread of variants that might not be efficiently inhibited by antibodies could undermine our current vaccination strategy,” says Stefan Pöhlmann, an infection biologist at the German Primate Center in Göttingen. Therefore, the team led by Pöhlmann and Münch investigated how effectively the mutant viruses are inhibited by drugs and antibodies.

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Study of coronavirus variants predicts virus evolving to escape current vaccines

vaccine

A new study of the U.K. and South Africa variants of SARS-CoV-2 predicts that current vaccines and certain monoclonal antibodies may be less effective at neutralizing these variants and that the new variants raise the specter that reinfections could be more likely.

The study was published in Nature on March 8, 2021. A preprint of the study was first posted to BioRxiv on January 26, 2021.

The study’s predictions are now being borne out with the first reported results of the Novavax vaccine, says the study’s lead author David Ho, MD. The company reported on Jan. 28 that the vaccine was nearly 90% effective in the company’s U.K. trial, but only 49.4% effective in its South Africa trial, where most cases of COVID-19 are caused by the B.1.351 variant.

“Our study and the new clinical trial data show that the virus is traveling in a direction that is causing it to escape from our current vaccines and therapies that are directed against the viral spike,” says Ho, the director of the Aaron Diamond AIDS Research Center and the Clyde’56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

“If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus,” Ho says. “Such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout.”

After vaccination, the immune system responds and makes antibodies that can neutralize the virus.

Ho and his team found that antibodies in blood samples taken from people inoculated with the Moderna or Pfizer vaccine were less effective at neutralizing the two variants, B.1.1.7, which emerged last September in England, and B.1.351, which emerged from South Africa in late 2020. Against the U.K. variant, neutralization dropped by roughly 2-fold, but against the South Africa variant, neutralization dropped by 6.5- to 8.5-fold.

“The approximately 2-fold loss of neutralizing activity against the U.K. variant is unlikely to have an adverse impact due to the large ‘cushion’ of residual neutralizing antibody activity,” Ho says, “and we see that reflected in the Novavax results where the vaccine was 85.6% effective against the U.K. variant.”

Data from Ho’s study about the loss in neutralizing activity against the South Africa variant are more worrisome.

“The drop in neutralizing activity against the South Africa variant is appreciable, and we’re now seeing, based on the Novavax results, that this is causing a reduction in protective efficacy,” Ho says. 

The new study did not examine the more recent variant found in Brazil (B.1.1.28) but given the similar spike mutations between the Brazil and South Africa variants, Ho says the Brazil variant should behave similarly to the South Africa variant. 

 “We have to stop the virus from replicating and that means rolling out vaccine faster and sticking to our mitigation measures like masking and physical distancing. Stopping the spread of the virus will stop the development of further mutations,” Ho says.  

The study also found that certain monoclonal antibodies used now to treat COVID patients may not work against the South Africa variant. And based on results with plasma from COVID patients who were infected earlier in the pandemic, the B.1.351 variant from South Africa has the potential to cause reinfection.

New study contains comprehensive analysis of variants

The new study conducted an extensive analysis of mutations in the two SARS-CoV-2 variants compared to other recent studies, which have reported similar findings. 

The new study examined all mutations in the spike protein of the two variants. (Vaccines and monoclonal antibody treatments work by recognizing the SARS-CoV-2 spike protein.)

The researchers created SARS-CoV-2 pseudoviruses (viruses that produce the coronavirus spike protein but cannot cause infection) with the eight mutations found in the U.K. variant and the nine mutations found in the South African variant.

They then measured the sensitivity of these pseudoviruses to monoclonal antibodies developed to treat COVID patients, convalescent serum from patients who were infected earlier in the pandemic, and serum from patients who have been vaccinated with the Moderna or Pfizer vaccine.

Implications for monoclonal antibody treatments

The study measured the neutralizing activity of 18 different monoclonal antibodies—including the antibodies in two products authorized for use in the United States. 

Against the U.K. variant, most antibodies were still potent, although the neutralizing activity of two antibodies in development was modestly impaired. 

Against the South Africa variant, however, the neutralizing activity of four antibodies was completely or markedly abolished. Those antibodies include bamlanivimab (LY-CoV555, approved for use in the United States) that was completely inactive against the South Africa variant, and casirivimab, one of the two antibodies in an approved antibody cocktail (REGN-COV) that was 58-fold less effective at neutralizing the South Africa variant compared to the original virus. The second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail.  

“Decisions of the use of these treatments will depend heavily on the local prevalence of the South Africa and Brazil variants,” Ho says, “highlighting the importance of viral genomic surveillance and proactive development of next-generation antibody therapeutics.” 

Reinfection implications

Serum from most patients who had recovered from COVID earlier in the pandemic had 11-fold less neutralizing activity against the South Africa variant and 4-fold less neutralizing activity against the U.K. variant.

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Tracking the global movement of malaria parasites and their variants

malaria

An international collaboration of researchers have developed a computational method to identify malaria parasites as they move around the world with their human hosts—key to measuring impact of elimination campaigns.

Led by University of Melbourne Professor Karen Day, Laboratory Head at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and Bio21, the team collected parasites from 23 locations in 10 countries.

Malaria is the world’s most deadly parasitic disease, killing over half a million people every year. It is hampered by drug resistance and the first recently developed vaccine offers only partial protection.

The team sequenced parasite DNA from 1,248 malaria infected patients and established a global database of 32,682 variant surface antigen genes, to track down to country level where parasites originated. Findings from the 10-year project were published in PLOS Genetics.

“In malaria, we have to deal with tens of thousands of variants in one endemic area. This database is a significant step forward in tracking those variants, and understanding how malaria is moving around the world,” Professor Day said.

“The impact of this is we can follow contemporary patterns of parasite migration in a cost-effective manner without having to sequence the whole genome. The signature of the past is very much visible in what we found but now we can see if anything changes. It gives us another window into how we can adapt parasite genomics to inform malaria surveillance.”

Professor Day said these evolutionary findings have translational implications in providing a diagnostic framework for geographical surveillance of malaria.

“It can also inform efforts to understand the presence or absence of global, regional and local population immunity to specific variants,” she said.

“Our next step would be to grow our database in the Asia -Pacific, with more collaborators and opportunities for regional training.”

An example of what Professor Day and her research team are striving towards is similar to ‘FluNet’, a global web-based tool for influenza surveillance by the World Health Organization.

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Pfizer says South African variant could significantly reduce protective antibodies

(This February 17 story corrects headline and first paragraph to show the reduction was in the protective antibodies elicited by the vaccine, not the protection of the vaccine overall)

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(Reuters) – A laboratory study suggests that the South African variant of the coronavirus may reduce protective antibodies elicited by the Pfizer Inc/BioNTech SE vaccine by two-thirds, and it is not clear if the shot will be effective against the mutation, the companies said on Wednesday.

The study found the vaccine was still able to neutralize the virus and there is not yet evidence from trials in people that the variant reduces vaccine protection, the companies said.

Still, they are making investments and talking to regulators about developing an updated version of their mRNA vaccine or a booster shot, if needed.

For the study, scientists from the companies and the University of Texas Medical Branch (UTMB) developed an engineered virus that contained the same mutations carried on the spike portion of the highly contagious coronavirus variant first discovered in South Africa, known as B.1.351. The spike, used by the virus to enter human cells, is the primary target of many COVID-19 vaccines.

Researchers tested the engineered virus against blood taken from people who had been given the vaccine, and found a two- thirds reduction in the level of neutralizing antibodies compared with its effect on the most common version of the virus prevalent in U.S. trials.

Their findings were published in the New England Journal of Medicine (NEJM).

Because there is no established benchmark yet to determine what level of antibodies are needed to protect against the virus, it is unclear whether that two-thirds reduction will render the vaccine ineffective against the variant spreading around the world.

However, UTMB professor and study co-author Pei-Yong Shi said he believes the Pfizer vaccine will likely be protective against the variant.

“We don’t know what the minimum neutralizing number is. We don’t have that cutoff line,” he said, adding that he suspects the immune response observed is likely to be significantly above where it needs to be to provide protection.

That is because in clinical trials, both the Pfizer/BioNTech vaccine and a similar shot from Moderna Inc conferred some protection after a single dose with an antibody response lower than the reduced levels caused by the South African variant in the laboratory study.

Even if the concerning variant significantly reduces effectiveness, the vaccine should still help protect against severe disease and death, he noted. Health experts have said that is the most important factor in keeping stretched healthcare systems from becoming overwhelmed.

More work is needed to understand whether the vaccine works against the South African variant, Shi said, including clinical trials and the development of correlates of protection – the benchmarks to determine what antibody levels are protective.

Pfizer and BioNTech said they were doing similar lab work to understand whether their vaccine is effective against another variant first found in Brazil.

Moderna published a correspondence in NEJM on Wednesday with similar data previously disclosed elsewhere that showed a sixfold drop antibody levels versus the South African variant.

Moderna also said the actual efficacy of its vaccine against the South African variant is yet to be determined. The company has previously said it believes the vaccine will work against the variant.

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