Omnibus Omicron Intelligence
Harvard Medical School experts on viral evolution, vaccines, the immune system—and what’s next
Can Omicron lead to long-COVID? How durable is current vaccine protection against severe disease? What are the new, state-of-the-art treatments for people who become infected? Between four and five hundred members of the Harvard Medical School (HMS) community convened via Zoom on Friday January 21—the day nearly 3,700 COVID deaths were reported in the United States, a level not seen since February 2021—to listen and speak to expert faculty colleagues about these and other key COVID questions—concerning the virus’s continuing rapid evolution, Omicron-induced immunity, the risks to unvaccinated pregnant women, vaccination for children under 5, and more.
Dean George Q. Daley introduced the panelists, all faculty members involved in the work of the Harvard-led Massachusetts Consortium on Pathogen Readiness (MCPR), a “multi-institutional collaboration uniting literally hundreds of scientists, clinicians, public health professionals in a common goal,” as he described it—“to confront SARS-CoV-2, and to address this global health crisis.” Earlier in the week, Daley noted, MCPR had announced an additional $8.5 million in funding to support 35 to 40 research projects in three new areas of focus: viral variants; long-COVID; and the collection of biospecimens to be shared among participating institutions. With this community meeting, he aimed to provide the most “transparent, evidence-based information possible about the latest science, the recent surge in cases, and…the evolving nature of the pandemic.”
Professor of medicine Galit Alter, who leads MCPR’s pathogenesis program, began by describing the more limited disease driven by the Omicron variant, which is active in the upper respiratory tract and appears not to travel as deeply into the lungs, particularly among the vaccinated. That is critical, because the COVID cases involving severe lung infection have been implicated in the most dangerous illnesses and risks of death. For vaccinated populations, “the data look quite good,” she said. But among the lingering questions is whether those individuals who do become sick are at risk for long-COVID, which has been debilitating for 10 to 20 percent of the individuals who contracted a previous variant.
And, she added, scientists are seeing severity of disease and death from Omicron in unvaccinated populations. That means that Omicron has the potential to be severe even in vaccinated individuals once their immunity begins to wane, underscoring the need to understand exactly how durable the vaccines really are, as well as the nature and duration of the protection conferred by prior infection. Genetic sequencing has shown that Omicron evolved directly from the first wave of SARS CoV-2, rather than as a descendant of more virulent, later strains, such as Beta in the United Kingdom, and then Delta, which fueled the fall surge in the United States. Hence, the question of whether infection with Omicron will protect against future variants that might be derived from these more dangerous variants is unknown.
A Rapidly Evolving Virus
The rapid evolution of the virus has surprised researchers more than once. Jacob Lemieux, instructor in medicine and co-lead of the MCPR viral variants program, noted that “when SARS CoV-2 first emerged, most people, myself included, didn’t expect this degree of evolution,” and therefore didn’t anticipate the impact that would have on the course of the pandemic. Now, he pointed out, the evolved ability of the virus to escape the immune system is actually driving the pandemic: witness the explosive spread of Omicron around the world. That immune evasion is characterized by the virus’s ability to escape antibodies, something that is particularly evident in the Omicron variant. (Neutralizing antibodies are the ones that prevent infection, and have been the focus of most media reports on the immunity conferred by vaccines or infection; but other arms of the immune system, such as T cells, are key to preventing severe illness and death.) Lemieux said he was hopeful that as immunity from vaccination and prior disease becomes widespread, “We’ll see more of an equilibrium” between immunity and the virus’s ability to replicate, which would cause the waves of disease to become less frequent and less severe.
Asked whether evolution of the virus has trended toward more transmissible and less virulent strains, Lemieux noted that the increased transmissibility has been a hallmark of each new variant. But changes in virulence have not shown such a clear pattern. The Beta and Delta variants both are more pathogenic than the original, while Omicron is milder than some of the other variants. “We have to remain on our toes,” he said, “because there is still a lot we don’t know about the virus.”
In the case of Omicron, the increased transmissibility of the virus has outweighed any diminishment in virulence: it has unleashed enormous numbers of infections, and even with a relatively low percentage of cases becoming severe, the absolute number of severe cases is huge. At hospitals across the country, intensive care units are full of COVID-19 patients who are either unvaccinated or are among the 5 to 7 percent of the population who are immunocompromised, and thus must rely on the good faith of others to wear masks and maintain distance to help protect them from infection. As assistant professor of Medicine Kathryn Stephenson, co-lead of the MCPR biospecimens program put it, “Omicron may be mild more often for the individual, but it certainly has not been mild” for the healthcare community.
Vaccines, T Cells, and Immunity
On a brighter note, Stephenson noted that the vaccines have held up surprisingly well. Their effectiveness against breakthrough infections has dropped from about 90 percent to perhaps 80 percent, she said, meaning that they are still amazingly effective. Her surprise that they still work comes from the fact that there are “dozens of mutations” in the virus at exactly the places where protective human antibodies bind. “When you test antibody responses in the laboratory, you see this evaporation of neutralization activity,” she reported. “If you just looked at the data, you would have predicted that these vaccines would have no effect whatsoever.” But they are working, and “I think it has to do with the fact that there is more to immune responses [to vaccines] than just antibodies.” T cell responses are one component of the immune system, for instance, that seem to be holding up well among vaccinated individuals.
T cells, explained Alter, are really “critical players in patrolling the immune system.” Once they identify cells as being infected, T cells eliminate them in a targeted way, to “curb disease as quickly as possible,” she said. “These mechanisms are shown to be critically important against many, many different viruses, including influenza, respiratory syncytial virus, as well as many bacterial infections, and they are critical for eliminating tumors.”
During the pandemic, “the T cell response has not gotten quite as much attention as antibodies,” Alter continued, “but it is clearly induced by many of these vaccines…and likely to be a key mechanism by which we still continue to respond to the virus.” Even when the vaccines fail to prevent infection, the T cell responses—and probably other immunological mechanisms—help clear the infection before it can cause disease. “We really need to continue to do research to truly understand exactly what level of T cells or other immune responses are required” she said, in order to know “when we need to boost folks again,” because even T cells can become quiescent over time without boosting.
COVID Case Care
Alongside vaccines, another bright point was reported by professor of medicine Rajesh Gandhi, who co-leads the MCPR clinical management and outcomes research program. The treatment regimens used to care for hospitalized COVID-19 patients remain effective and have not changed much in the past year and a half (see “The State of the Pandemic” for a description of these protocols).
But physicians now have “four new treatments in our armamentarium” for outpatient care, he reported. First is Paxlovid, a combination of an investigational antiviral drug developed by Pfizer, and an antiretroviral often used to treat HIV. The drug is administered orally, and cuts the chance of hospitalization and death by 90 percent in high-risk individuals (although interactions between other medications and the antiretroviral component prevents its use in some cases). Next best is a monoclonal antibody treatment called sotrovimab, the only one of the three monoclonal antibody products that has remained effective against Omicron. A third type of treatment is remdesivir, used most often for hospitalized patients because it must be administered intravenously on three consecutive days. “Last on the list because it is not as efficacious as the other three,” reported Gandhi, is molnupiravir. The drug is “around 30 percent effective when it comes to preventing hospitalization and death” and therefore is typically used only when none of the other three are available.
Supplies of these wonder drugs are limited, however. For example, Gandhi reported, Massachusetts received just 1,000 doses of Paxlovid in its first shipment during a week when the state recorded 56,000 cases of COVID-19. Massachusetts General Hospital, where he works, and hospitals throughout the Commonwealth, have therefore been prioritizing the highest-risk individuals: those who are immunocompromised and/or over the age of 75; and those over the age of 65 who have another condition that puts them at risk. As supplies increase, he noted, it may turn out that these antivirals will play a role in preventing long-COVID—“but that has yet to be established.”
Long-COVID and Children’s Health
Long-COVID—persistent symptoms or damage that can last months or even longer—is still being defined as a syndrome. The National Institutes of Health, said Gandhi, has invested in a concerted effort to characterize the affliction, and a number of Harvard institutions are prominently involved in a study to try to understand the frequency and mechanisms behind it. Among the hypotheses for a cause, one is hyper inflammation. “We know that COVID can trigger immune dysregulation. Is that why some people have persistent symptoms?” he asked. Another theory revolves around autoimmunity. “Again,” he continued, “there are important data that suggest that some individuals can develop autoimmunity or an immune response directed against their own cells and tissues.” A third possible explanation, among others, is viral persistence in the body, which might then “be amenable to either vaccine-induced clearance or antivirals.”
Pediatric cases of long-COVID, reported Alter, are driving the effort to deploy vaccines for children under five. Both Pfizer and Moderna, she said, are working to determine the proper dose for young children—“the immunogenicity profiling looks wonderful.” Alter, who led efforts early in the pandemic to establish that vaccines are safe and effective for pregnant women—otherwise at high risk for severe COVID-19—also took the opportunity to emphasize that the vaccines induce especially “robust immune responses” in this population “that are then transferred to the infant in the first few days of life when they are not able to get a vaccine.”
Alter noted that both mRNA vaccine manufacturers (Pfizer and Moderna) have already generated formulations that target variants, now in the testing and certification phase. Now the question is can they be rolled out like the annual flu vaccine, without “having to redo efficacy studies every single time,” she said, “which is really just not feasible” given the time that takes compared to the rapidity with which the virus changes. And further in the future, she acknowledged, are pan-coronavirus vaccines, now in development, designed to be applied across the viral spectrum sufficiently broadly so developers won’t have to chase each new variant with a tweaked formula.
Pandemic Prospects and Personal Safety
Clearly, the pandemic is not over; vaccines have not reached everyone who wants them—especially in the less affluent parts of the world—and effective treatments are in short supply.
What practical advice can people follow to keep themselves and those in their community safe? For those answers, Dean Daley turned to associate professor of systems biology Michael Springer, whom Daley had noted earlier in his introductory remarks is the person responsible for developing Harvard’s unique nasal swab collection device, and the high throughput automated processing of Harvard student, faculty and staff PCR tests that takes place in Harvard labs.
Springer updated earlier findings, based on contact tracing and genetic sequencing, that Harvard’s classrooms remained among the safest places to be, even during the initial Omicron surge during December exams. With upgraded ventilation and a mask requirement for students, coupled with regular testing and contact tracing then in effect, “There is no evidence of any transmission actually happening” in classrooms.
The risky situations occur when people remove masks on public transportation, or in restaurants or grocery stores. “If you wear a mask and wear it properly, you are largely protected,” he said. “Try to stay distanced from other people as much as possible.” But, he acknowledged, “When the case loads are as high as they are now, it is hard to avoid exposure. Expectations are that a third to half of us will get Omicron by the middle of February.”
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