The Case for Cautious COVID Optimism This Winter

At this time last year and two years ago, daily new infections and COVID-related hospitalizations were already accelerating at a fast clip. BQ.1 and BQ.1.1, the latest Omicron subvariants, came to comprise the majority of cases during a relative lull in the pandemic. Combined with a Thanksgiving Holiday that saw the most travelers since the pandemic started, there has been a steady increase in COVID metrics.

However, there are many reasons to be optimistic. A combination of factors—a high level of population immunity, Omicron family antigenic drift, convergence of mutations that seem to have hit an evolutionary ceiling, almost nonexistent severe COVID illness in the hospital, and viral interference from RSV and Influenza surges—means we are in a surprisingly good place with COVID-19 in winter 2022-23.

Antigenic drift

The first two pandemic years were marked by surge after surge driven by variants of entirely new lineages. But since South African researchers first identified Omicron one year ago, we have seen subvariants exclusively from that lineage. This antigenic drift, while spawning an alphabet soup of approximately 500 subvariants, has actually generated less and less impactful waves as population level immunity to Omicron grew. The most recent summer wave driven by BA.4 and BA.5 did not lead to a significant surge of hospitalizations or deaths in the U.S.

Before the Omicron winter surge a year ago, only 1 in 3 people in the U.S. had been infected with COVID-19. By the end of February, that number was 60%—and certainly much higher now at the end of 2022. It’s safe to say a lot of immune systems have “seen” Omicron by this point on top of a vaccination rate of 73% in those 5 and older. As long as there is not a dramatic antigenic shift to an entirely new lineage, there are very little new tricks Omicron can throw our way. But, if such a shift were to happen, our T-cells and memory B-cells will continue to provide robust protection against severe disease from new variants.

Evolutionary ceiling

Recent research showed marked resistance of the BQ.1. and BQ.1.1 subvariants (among others) to neutralizing antibodies in the sera of both triple-vaccinated and those recently infected with BA.1 and BA.5. This immune evasiveness is due to a key N460 mutation in the spike protein of BQ.1 and BQ.1.1 and to a lesser extent, R346t and N658S mutations.

The new Omicron subvariants are accruing mutations at a breakneck speed that in theory give them an exponential growth advantage over their BA.2 and BA.5 parentage. But interestingly, the multiple subvariants are converging on the same mutations. Despite their demonstrated immune evasiveness prowess in the lab, they have not led to significant waves in countries where they become dominant.

The XBB variant achieved dominance in Singapore earlier this Fall. XBB is a descendant of BA.2 but differs by 8 key spike mutations. Despite these apparent growth advantages, XBB did not lead to a major surge in hospitalizations or deaths in Singapore.

Although important to tread carefully when comparing countries, France’s recent experience with BQ.1.1 likely provides insight into how that variant will play out here. France and the U.S. share a lagging updated bivalent booster rate for those at higher risk for severe COVID illness (older individuals)—approximately 30% of those 65 years or older in both countries have received the updated booster. BQ.1.1 became dominant in France at the end of October but has not led to a surge in hospitalizations or ICU admissions.

So, a convergence of rapidly accruing mutations demonstrating immune evasiveness in the lab has not generated a surge in infections or hospitalizations in the real world. This certainly begs the question: has SARS-COV-2 hit an evolutionary ceiling in the face of our high population immunity?

Where have severe COVID-19 patients gone?

We rarely encounter patients with severe COVID in the ED or hospital wards now, in sharp contrast to the winter of 2020. By severe COVID, we are referring to patients with viral pneumonia and hypoxia requiring various oxygen-delivery and ventilation systems and strategies, intravenous decatron and other complicated immune-modulating medications, and the involvement of respiratory therapists and multiple medical specialists.

The majority of states and county public health departments still do not delineate COVID-19 hospitalizations between those admitted primarily for COVID vs. those who incidentally test positive. The CDC in fact in September advised that hospitals could stop routine pre-admission testing for COVID. But many hospitals and health care systems have been reluctant to relinquish this outdated practice. As such, given the ability of BQ.1 and BQ.1.1 to evade neutralizing antibodies, we expect an increase in country-level hospitalization numbers this winter due to incidental positives, but we should be reassured that the vast majority will not be for severe COVID illness.

In fact, since the advent of Omicron, multiple studies have demonstrated that Omicron is just not very good at infecting lung tissue. As early as January 2022, we had multiple laboratory studies showing that Omicron had an affinity for replicating rapidly in the upper airways but markedly less tropism for alveolar lung cells. This viral evolutionary trade-off likely explains how a large Kaiser Southern California study comparing 223,000 Omicron infections to 23,000 Delta variant infections found that those infected with Omicron had significantly less risk of severe illness and shorter hospital stays. And a new South African study shows that the risk of hospitalization and mortality declined even further from the BA.1/BA.2 wave to the BA.4/5 wave.

Viral interference

RSV has led a troupe of viral respiratory illness in children that has quickly overwhelmed children’s hospitals and flooded emergency rooms across the country. At the same time, as we observed in the Southern Hemisphere countries, the influenza season kicked off approximately two months earlier than usual. As of the most recent CDC FluView report, there have already been over 6.2 million flu illnesses, 53,000 hospitalizations and 2,900 deaths. Flu is being driven by the more virulent Flu A strain, 78% of which has been H3N2, which is known to cause more severe illness in children and the elderly.

Importantly, the U.K. reported this past week that ICU admissions for flu exceeded those for COVID for the first time during the pandemic. This is likely due to the reduced severity of COVID and high level of population immunity as well as the dominance of the Flu A (H3N2) strain.

The early surges of RSV and flu raises the interesting question of viral interference. Is it possible that earlier-than-usual surges in RSV, flu, and other viral respiratory illnesses are crowding out covid this year? A growing body of both epidemiological and laboratory data suggest that the dreaded tripledemic is unlikely. One theory points to chemical messengers triggered by a viral infection called interferons that generate a population level immunity barrier against another virus. For the first two years of the pandemic, non-COVID viral illness was crowded out by COVID. This winter, the opposite could be occurring. Of note, this resurgence of endemic viruses, such as influenza and RSV, as population immunity rose to COVID and with decreased immunity to other viruses over the past 2.5 years, was predicted in June 2020.

New vax effective especially at extended intervals

Lastly, we finally have real-world data on the effectiveness of the new bivalent COVID booster. While the CDC study did not answer the question of whether the bivalent booster is better than another dose of the original vaccine recipe, the bivalent booster provides protection against symptomatic infection from BA.5. And the study clearly demonstrated that a longer gap between doses generated a bigger immune boost; we advocated for a 6-month extended interval in a recent piece in TIME. Older individuals in the US need the COVID booster (and a higher influenza vaccine dose) the most given a less robust immune response populations 65 and older.

What next?

We are in good shape as we head into this third pandemic winter with BQ.1 and BQ.1.1 holding the reins. This does not mean we will rest on our laurels.

For the first time, we do not have an effective monoclonal antibody treatment for those immune-compromised or high-risk for severe covid illness. Both BQ.1. and BQ.1.1 are resistant to our last effective monoclonal antibody treatment, bebtelovimab. We urgently need an armamentarium of second-generational monoclonals that can supersede the convergence of immune evasive mutations exhibited by the Omicron subvariants.

Nearly 9 in 10 COVID deaths are in people 65 or older. However only 32% of this group has received an updated bivalent booster. Paxlovid use in this group is also woeful despite evidence that this age group benefits the most from its use. Older individuals need ongoing boosting and treatment as we enter COVID endemicity in this third winter living with this now not-so-novel coronavirus.