This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.
In the spring of 2020, the city of Manaus, 200 miles south of the equator in the heart of Brazil’s Amazon, was hit hard by the first wave of the COVID-19 pandemic. Researchers calculated that 70 percent of the population was infected with SARS-CoV2.
The silver lining to the massive scale of the outbreak in the city, experts thought, was that such a high level of infection would confer herd immunity, a population-level defense against another outbreak of the disease.
But in December, another large wave of the virus hit the people of Manaus and, as infections rose, hospitalizations and deaths began to climb. The second wave was just as severe as the first.
The December surge corresponded with the emergence of a new strain of the virus, named P.1, which raised concerns that this new strain might have found ways to evade the defenses against the virus that people acquired with the first round of infections earlier in the spring.
Around the world, scientists and clinicians have been studying this and other mutant strains, tweaking vaccine formulations to improve protection against the variants, and developing diversified, flexible treatments to respond to the new lineages of SARS-CoV-2, known as “variants of concern” that are spreading around the world.
To highlight the evolving understanding of new and emerging SARS-CoV-2 variants, the Harvard Medical School-led Massachusetts Consortium on Pathogen Readiness (MassCPR) convened on Feb. 24 a panel of virologists, vaccinologists, immunologists, infectious disease physicians and other experts to discuss what the new variants mean for efforts to contain the pandemic, to optimize vaccines, and to enhance physicians’ therapeutic arsenals.
Novel state of contagion?
In his opening remarks, George Q. Daley, dean of HMS, said that while the toll of the pandemic has been extraordinary, the unprecedented scientific and medical progress marshaled to fight the pandemic has also been extraordinary, with astonishingly fast progress from identification of the first genotype of the virus to emergency approval of the first vaccine in just one year.
But he also issued a strong note of caution.
“While we in the medical community are guardedly hopeful and optimistic that the vaccines promise the end of the current pandemic,” Daley said, “there is cause for concern that with the appearance of viral variants across the globe, we might be facing a decidedly novel stage of contagion, COVID-19 2.0.”
Daley was joined in the virtual presentation by a panel of experts from MassCPR who discussed the process of viral evolution and the forces driving the mutations that could help the virus spread more quickly in human populations, could cause more severe illness, or could defeat defenses against the disease.
They outlined how scientists are studying the impact of the variants on infectivity, vaccination efforts, and treatment of the disease, describing strategies being adopted to respond to the newer forms of the virus.
For SARS-COV-2 to infect a human, the spiky proteins in its eponymous crown dock with receptors on the surface of respiratory cells in the nose and lungs.
As trillions of copies of the virus are made in infected people around the world, sometimes typos or copy and paste errors appear in its genome, which is one reason it’s crucial to slow down infections and stop the spread of the virus through measures like mask-wearing while waiting for the vaccine to be widely delivered, the experts said.
“One of the amazing things about the COVID-19 story over the past year is that there are virologists all around the planet who have been sequencing the genomes of the viruses that are infecting people, so we have tens of thousands of sequences, each of which gives us a fingerprint of the virus that is infecting that person or that community,” said Jeremy Luban, a professor in the Program in Molecular Medicine and the Department of Biochemistry and Molecular Pharmacology at the University of Massachusetts Medical School. Luban studies viral replication, pathogenesis, and immunity.
Many mutations either have no effect or cause changes that inhibit the virus from replicating or infecting humans.
As scientists around the world continuously sample the genomes of infectious individuals, Luban said, they find many variants that appear only once or in brief flashes in a small population before they disappear, outcompeted and overwhelmed by the predominant strains.
But a few mutations do change the virus in ways that make it easier for it to survive and spread.
It might happen by making the bond between virus and human cells tighter, or by changing the shape of the proteins that antibodies use to target the virus, the researchers said.
In these cases, instead of appearing as a brief blip on the radar screen of genomic surveillance, these mutations thrive and spread, showing up more and more often as they grow to greater and greater prevalence in the population.
The mutations that spread rapidly, including P.1, the B.1.351 variant detected in South Africa, and B.1.1.7, first found in the United Kingdom, are dubbed variants of concern.
Since the spike protein is key to both infection and immune response, Luban noted that mutations to the spike might make variants simultaneously more infectious while also making it harder for the immune system to defend against the attack.
“One of the concerns that we have is that these mutations in the spike may permit the virus to escape from the immune control that has been established in a person from a prior infection or perhaps from a vaccine,” Luban said.
So far, the evidence that existing vaccines still provide considerable protection against the known variants is reassuring, said Galit Alter, professor of medicine at HMS and Massachusetts General Hospital, principal investigator of the Ragon Institute of MGH, MIT and Harvard, and an immunologist who co-leads the pathogenesis working group of MassCPR.
For the past year, Alter has focused her work on unraveling the fundamental mechanisms that underlie COVID-19 and on how SARS-CoV-2 interacts with the host to cause disease.
Alter said that while some of the variant strains have increased resistance to some of the vaccines, all of the vaccines currently in use retain strong blocking action against all known variants to date.
The vaccines that have been administered in the UK and South Africa, where the variants have become abundant, are still providing significant protection for people who were vaccinated before the new strains were discovered, Alter said.
This is likely because the immune system makes many different antibodies that attack many different sites on the virus, making it unlikely that a single variant would be able to defeat all of those antibodies, and because the immune system has other weapons against the virus besides antibodies, including T cells, Alter said.
Instead of attacking the virus, T cells remove infected cells from the body to prevent them from creating more copies of the virus. T cells induced by the vaccine do not seem to have lost any of their ability to fight an infection caused by variant strains of the virus, she said.
The next question will be whether the vaccines are as effective at preventing infection and transmission as they are at preventing serious disease, Alter said.
If vaccines prevent serious disease but do not prevent transmission, then an effective global vaccination campaign can turn COVID-19 into something like the common cold. But some emerging data suggest that the vaccines also prevent transmission, which means that mass vaccinations may be able to stop the widespread prevalence of the virus and slow down both the severe illness that is currently experienced as well as the evolution of new variants.
Scientists are also taking advantage of the wealth of genomic and structural data available about the virus to develop next-generation vaccines with the goal of producing highly flexible vaccines that use different mechanisms to provide immunity to all known variants, Alter said, noting that there are already more vaccine varieties for this virus than for any other virus that has ever existed.
Jonathan Abraham, an HMS assistant professor of microbiology who co-leads the therapeutics working group of MassCPR, discussed the importance of getting ahead of viral mutations through pan-coronavirus therapeutics, small-molecule therapies, and diversified cocktails of monoclonal antibodies.
To make monoclonal antibodies, the antibodies found in the blood of people who have recovered from COVID-19 are replicated en masse and administered intravenously.
To fight strains resistant to certain antibodies, new cocktails will need to be developed that can continue to block the mutated virus, Abraham said.
SARS-CoV-2 has a very, very large genome, and requires many complex proteins to infect cells and spread. Abraham noted that the pharmaceutical industry has had great success in targeting this type of protein with small molecules that insert themselves into the protein models and short-circuit the virus’s ability to replicate.
One such small-molecule drug, the broad-spectrum antiviral remdesivir, has already been given FDA approval for use against COVID-19.
Remdesivir, like many of the existing therapies in its category, must be administered by injection. However, there are new classes of small-molecule drugs that can be administered as pills and these are causing great excitement in the field as potential therapies for COVID-19, Abraham said.
These kinds of drugs, however, take longer to develop than monoclonal antibodies, Abraham said, but they have the advantage of targeting proteins less likely to change through the mutation process that creates new strains of the virus.
That means once developed, these drugs will likely provide flexible, durable treatments against a variety of variants of SARS-CoV-2 and other coronaviruses.
Many kinds of response
Following the presentations, the speakers were joined by a panel, including the faculty co-leads of Mass CPR, Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the HMS Department of Immunology, and Bruce Walker, HMS Phillip T. and Susan M. Ragon Professor of Medicine at Mass General, Mark Namchuk, executive director of therapeutics translation at HMS and co-leader of the MassCPR therapeutics working group, Lindsey Baden, HMS associate professor of medicine at Brigham and Women’s Hospital and the anchor of the phase 3 Moderna COVID-19 vaccine trial, and Dan Barouch, HMS William Bosworth Castle Professor of Medicine at Beth Israel Deaconess Medical Center, who developed the Ad26 viral vector that is the foundation of the Johnson & Johnson vaccine for COVID-19, which is expected to receive FDA emergency-use approval shortly.
Walker and Barouch noted the importance of using vaccines to elicit as many different kinds of immune response as possible, particularly in the face of an evolving virus.
“Just like you wouldn’t want to fight with one hand behind your back, I think for this virus we really want all aspects of the immune response triggered by vaccines,” Barouch said. “I think that’s particularly important for viral variants that might knock out or severely reduce one or another type of immune response.”
The speakers highlighted some challenges to the effort to confront the evolving strains of the virus, including a lack of genomic surveillance in the U.S.
In the U.K., 1 in 10 cases is genotyped, they said, giving a good view of which versions of the virus are spreading and whether new strains are emerging, but in the U.S., less than 1 in 100 cases is genotyped, and the genotyping is not evenly distributed across the country.
Scientists can’t prepare for or respond to new variants if they don’t know what’s coming, the researchers said.
They also mentioned the importance of coordinated national and international efforts, and of universal access to health care and education, because the virus is not limited by international borders and can spread easily from small pockets of infection.
But the researchers also emphasized the remarkable progress that has been made against the virus and all its variant forms.
Daley noted that, in spite of the great devastation that the virus has wrought, and the great uncertainty that lies ahead, the scientific community is confident that the current array of vaccines will prove effective, even in the face of the emerging variants.
“And if they don’t, we are ready to confront whatever comes our way,” Daley said, noting that there are strategies in place for developing the next generation of vaccines to be even more effective against the variants, with the ultimate goal of creating a single vaccine that can provide strong, durable protection against all strains of the virus. Efforts are also being made to develop a diverse array of more flexible and more effective therapies to treat the sick.
In the meantime, Daley emphasized that the world has months to go before herd immunity is achieved, and so it is crucial to continue to follow the critical public health measures that will slow the spread of the disease while the vaccines are being deployed.
“We hope sometime in the not-too-distant future we’ll be able to tell an even more optimistic story,” he said.