Virus World

Vaccines and prior infection still prevent severe disease from new SARS-CoV-2 strains.  Once again, South Africa is at the forefront of the changing COVID-19 pandemic. Epidemiologists and virologists are watching closely as cases there rise sharply again, just 5 months after the Omicron variant caused a dramatic surge. This time, the drivers are two new subvariants of Omicron named BA.4 and BA.5, which the Network for Genomic Surveillance in South Africa first detected in January. The new strains didn’t have much of an impact initially, but over the past few weeks case numbers in South Africa jumped from roughly 1000 per day on 17 April to nearly 10,000 on 7 May. A third subvariant called BA.2.12.1 is spreading in the United States, driving increases along the East Coast. It’s still unclear whether the new subvariants will cause another global COVID-19 wave. But like the earlier versions of Omicron, they have a remarkable ability to evade immunity from vaccines, previous infection, or both—a disturbing portent for the future of the pandemic and a potentially serious complication for vaccine developers. In most cases, vaccination or earlier infection still seem to provide protection from severe disease. “There’s no reason to freak out,” says John Moore, an immunologist at Weill Cornell Medicine. The new strains are “an additional hassle,” he says, but “there’s no indication that they’re more dangerous or more pathogenic.” Hospitalizations in South Africa, for example, have increased, “but because it is starting from a very low level, it’s not cause for alarm,” says virologist Tulio de Oliveira of Stellenbosch University, who helped identify BA.4 and BA.5. Numbers of patients in intensive care units are as low as they have been since the start of the pandemic, he says. “At the moment, we expect something similar to the Omicron BA.1 wave,” when hospitalization rates stayed manageable. The new superspreaders do, however, showcase the restless virus’ ability to find ways around the “immunity wall” built up over the past 2 years and to continue to circulate at high levels. Even if the new variants cause relatively little severe disease, “it’s a numbers game,” says Leif Erik Sander, an infectious disease expert at the Charité University Hospital in Berlin; enough new infections could still overwhelm health systems.

All three new strains share key mutations with the BA.2 strain of Omicron, which, like BA.1, emerged in southern Africa in October 2021. Initial studies by de Oliveira and Alex Sigal, an infectious disease expert at the Africa Health Research Institute in Durban, suggest BA.4 and BA.5 can elude the immunity of patients who were infected with the BA.1 strain, which in South Africa caused a much larger wave than BA.2. That may be in part because immunity has waned since South Africa’s BA.1 wave peaked in December. People who were both vaccinated and infected had somewhat stronger protection, de Oliveira and Sigal reported in a 2 May preprint. All three new variants have mutations that alter a key amino acid called L452, which may help explain their ability to dodge immunity. L452 is part of the receptor-binding domain, the part of the spike protein that locks onto cells, enabling infection. The domain is also a key target for protective antibodies. The Delta variant that caused devastating surges around the world in 2021 had mutations in L452 as well, so many scientists have been watching this hot spot carefully, including immunologist Yunlong Richard Cao of Peking University. On 11 April, Cao says, he and his colleagues noticed a pattern: New Omicron sublineages from New York, Belgium, France, and South Africa all had changes in L452. “The independent appearance of four different mutations at the same site? That’s not normal,” Cao says. The researchers suspected it was the virus’ response to the high levels of immunity generated by the huge Omicron waves. They immediately started to make copies of the spike protein based on the new sequences and test how well different antibodies could block those proteins, preventing them from binding to cells. They used sera from 156 vaccinated and boosted subjects, including some who had recovered from either BA.1 or severe acute respiratory syndrome (SARS), the coronavirus disease that caused a deadly global outbreak almost 2 decades ago. Like the South African team, they found that blood from patients who had been infected with BA.1 had only weak ability to neutralize BA.4 and BA.5; the same was true for BA.2.12.1. Even less effective were sera from people who had previously been infected with SARS and then vaccinated against COVID-19, they reported in a 2 May preprint.

The latter finding was surprising. Previous work by Linfa Wang, a bat coronavirus researcher at the Duke-NUS Medical School in Singapore, had shown patients who had recovered from SARS and were then vaccinated had strong protection against earlier SARS-CoV-2 variants—and even some related animal viruses—a finding that seemed to hold clues to developing vaccines effective against multiple coronaviruses, including those that might trigger the next pandemic. But the new mutations apparently helped the Omicron subvariants evade those previously powerful antibodies. Wang notes, however, that the subjects in the new study were all vaccinated with CoronaVac, a Chinese vaccine made from inactivated virus. Subjects in his study were vaccinated with messenger RNA (mRNA) vaccines, which might provide a more potent response to the new strains, he says. But Wang agrees that Omicron’s knack for immune escape is dramatic. Based on its immunological profile, it  “should be called SARS-3,” he says—an entirely distinct virus. Omicron’s rapid evolution creates difficult decisions for vaccine- and policymakers about whether to shift to a new set of vaccines or stick with the current formulations, which are based on the virus that emerged in Wuhan, China, more than 
2 years ago. Moderna has tested two versions of its mRNA vaccine, containing the ancestral strain and either the Beta variant—which spread in South Africa for a while in 2021 but is now gone—or the Omicron BA.1 variant. The company has not yet reported data on how well they might protect against the new subvariants. Pfizer, the other mRNA vaccine producer, has tested the efficacy of a booster and a primary vaccine based on BA.1. Results are expected by the end of June. The U.S. Food and Drug Administration has scheduled a meeting for 28 June to analyze available data and make vaccine recommendations for the fall.

The limited protection that BA.1 infection provided against the new subvariants in lab studies has already raised questions about how useful the new Omicron-specific vaccines might be. Wang says the virus is evolving too quickly for strain-specific vaccines to keep up. Instead, a broad cocktail of monoclonal antibodies targeting different strains might be the best way forward, he says. Such a shot could prevent infections for several months in those vulnerable to severe disease, including immunocompromised people who don’t respond to vaccines. Protecting that group is crucial, he notes, because many researchers suspect new variants emerge during long-term infections in people whose immune systems fail to clear the virus. The main hurdle, Wang says, is cost: A dose of monoclonal antibodies is about $1000 per patient, he notes, “but if someone could find a way to lower that to $50 or $100,” the approach could be cheaper than constantly updating vaccines. Kristian Andersen, who studies viral evolution at Scripps Research, draws a sobering lesson from the newest Omicron variants. Although we don’t know what future variants will look like, he says, “we can be certain that they’ll continue to be more and more capable of immune escape,” possibly leading to lower protection against not just infection, but also against severe disease. “We need to focus on broadening our immunity,” he says. It’s far from clear what kind of vaccine might prompt that broadened immunity, but “we really, really need to get going” to figure that out, Andersen says. “Simply letting the virus do what viruses do—continue to infect us, and likely several times a year—just isn’t an option in my playbook.”

Published in Science (May 10, 2022):

https://doi.org/10.1126/science.adc9473 

New research at Washington University School of Medicine in St. Louis indicates that three new, fast-spreading variants of the virus that cause COVID-19 can evade antibodies that work against the original form of the virus that sparked the pandemic. With few exceptions, whether such antibodies were produced in response to vaccination or natural infection, or were purified antibodies intended for use as drugs, the researchers found more antibody is needed to neutralize the new variants.  The findings, from laboratory-based experiments and published March 4 in Nature Medicine, suggest that COVID-19 drugs and vaccines developed thus far may become less effective as the new variants become dominant, as experts say they inevitably will. The researchers looked at variants from South Africa, the United Kingdom and Brazil. "We're concerned that people whom we'd expect to have a protective level of antibodies because they have had COVID-19 or been vaccinated against it, might not be protected against the new variants," said senior author Michael S. Diamond, MD, Ph.D., the Herbert S. Gasser Professor of Medicine. "There's wide variation in how much antibody a person produces in response to vaccination or natural infection. Some people produce very high levels, and they would still likely be protected against the new, worrisome variants. But some people, especially older and immunocompromised people, may not make such high levels of antibodies. If the level of antibody needed for protection goes up tenfold, as our data indicate it does, they may not have enough. The concern is that the people who need protection the most are the ones least likely to have it."

The virus that causes COVID-19, known as SARS-CoV-2, uses a protein called spike to latch onto and get inside cells. People infected with SARS-CoV-2 generate the most protective antibodies against the spike protein. Consequently, spike became the prime target for COVID-19 drug and vaccine developers. The three vaccines authorized by the Food and Drug Administration (FDA) for emergency use in the U.S.—made by Pfizer/BioNTech, Moderna and Johnson & Johnson—both target spike. And potent anti-spike antibodies were selected for development into antibody-based drugs for COVID-19. Viruses are always mutating, but for nearly a year the mutations that arose in SARS-CoV-2 did not threaten this spike-based strategy. Then, this winter, fast-spreading variants were detected in the United Kingdom, South Africa, Brazil and elsewhere. Sparking concern, the new variants all carry multiple mutations in their spike genes, which could lessen the effectiveness of spike-targeted drugs and vaccines now being used to prevent or treat COVID-19. The most worrisome new variants were given the names of B.1.1.7 (from the U.K.), B.1.135 (South Africa) and B.1.1.248, also known as P.1 (Brazil).

To assess whether the new variants could evade antibodies made for the original form of the virus, Diamond and colleagues, including first author Rita E. Chen, a graduate student in Diamond's lab, tested the ability of antibodies to neutralize three virus variants in the laboratory. The researchers tested the variants against antibodies in the blood of people who had recovered from SARS-CoV-2 infection or were vaccinated with the Pfizer vaccine. They also tested antibodies in the blood of mice, hamsters and monkeys that had been vaccinated with an experimental COVID-19 vaccine, developed at Washington University School of Medicine, that can be given through the nose. The B.1.1.7 (U.K.) variant could be neutralized with similar levels of antibodies as were needed to neutralize the original virus. But the other two variants required from 3.5 to 10 times as much antibody for neutralization. Then, they tested monoclonal antibodies: mass-produced replicas of individual antibodies that are exceptionally good at neutralizing the original virus. When the researchers tested the new viral variants against a panel of monoclonal antibodies, the results ranged from broadly effective to completely ineffective. Since each virus variant carried multiple mutations in the spike gene, the researchers created a panel of viruses with single mutations so they could parse out the effect of each mutation. Most of the variation in antibody effectiveness could be attributed to a single amino acid change in the spike protein. This change, called E484K, was found in the B.1.135 (South Africa) and B.1.1.248 (Brazil) variants, but not B.1.1.7 (U.K.). The B.1.135 variant is widespread in South Africa, which may explain why one of the vaccines tested in people was less effective in South Africa than in the U.S., where the variant is still rare, Diamond said. "We don't exactly know what the consequences of these new variants are going to be yet," said Diamond, also a professor of molecular microbiology and of pathology & immunology. "Antibodies are not the only measure of protection; other elements of the immune system may be able to compensate for increased resistance to antibodies. That's going to be determined over time, epidemiologically, as we see what happens as these variants spread. Will we see reinfections? Will we see vaccines lose efficacy and drug resistance emerge? I hope not. But it's clear that we will need to continually screen antibodies to make sure they're still working as new variants arise and spread and potentially adjust our vaccine and antibody-treatment strategies."

Original Findings Published in Nature Medicine (March 4, 2021):

https://doi.org/10.1038/s41591-021-01294-w

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear.

Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations.

Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

Preprint available at bioRxiv (July 22, 2020):

https://doi.org/10.1101/2020.07.21.214759

Following the emergence of SARS-CoV-2 in China in late 2019 a number of variants have emerged, with two of these – Alpha and Delta – subsequently growing to global prevalence. One characteristic of these variants are changes within the Spike protein, in particular the receptor binding domain (RBD). From a public health perspective these changes have important implications for increased transmissibility and immune escape; however, their presence could also modify the intrinsic host-range of the virus. Using viral pseudotyping we examined whether the variants of concern (VOCs) Alpha, Beta, Gamma and Delta have differing host ACE2 receptor usage patterns, focusing on a range of relevant mammalian ACE2 proteins. All four VOCs were able to overcome a previous restriction for mouse ACE2, with demonstrable differences also seen for individual VOCs with rat, ferret or civet ACE2 receptors, changes which we subsequently attribute to N501Y and E484K substitutions within the Spike RBD.

Preprint Available in bioRxiv (Nov. 24, 2021):

https://doi.org/10.1101/2021.11.23.469663

Newly emerging, fast-spreading variants of the coronavirus might reduce the protective effects of two leading vaccines. Michel Nussenzweig at the Rockefeller University in New York City and his colleagues analysed blood from 20 volunteers who received two doses of either the vaccine developed by Moderna or that developed by Pfizer–BioNTech (Z. Wang et al. Preprint at bioRxiv https://doi.org/frdn; 2021). Both vaccines carry RNA instructions that prompt human cells to make the spike protein that the virus uses to infect cells. This causes the body to generate immune molecules called antibodies that recognize the spike protein. Three to 14 weeks after the second jab, the study participants developed several types of antibody, including some that can block SARS-CoV-2 from infecting cells. Some of these neutralizing antibodies were as effective against viruses carrying certain mutations in the spike protein as they were against widespread forms of the virus. But some were only one-third as effective at blocking the mutated variants. Some of the mutations that the team tested have been seen in coronavirus variants that were first identified in the United Kingdom, Brazil and South Africa; at least one of these variants is more easily transmitted than other forms of the virus now in wide circulation. The findings suggest that vaccine-resistant variants might emerge, meaning that COVID-19 vaccines could need an update. They have not yet been peer reviewed.