We need a definitive exit from our Covid-19 pandemic. Here’s the roadmap | Eric Topol

As the virus accelerates it evolution, the humans capitulate. For two and a half years, the virus has been outrunning our response, getting progressively more and more transmissible, reaching a level of infectiousness that few pathogens have ever attained. Instead of taking a stance of getting ahead of the virus, and out-smarting it, people have succumbed.

In recent months, we experienced a striking jump in transmissibility when the Omicron (BA.1) variant became dominant with at least a threefold increase in reproductive number beyond Delta. Despite the hope that this might be reaching the upper limit of the virus’s spread ability, we quickly transitioned to a BA.2 wave with another jump of about 30% transmissibility, and now we are heading, in the United States, to a dominant subvariant known as BA.2.1.2.1, which is 25% more transmissible than BA.2 and already accounting for close to 50% of new cases.

This surely constitutes a meaningful acceleration of the virus’s evolution. There have been thousands of variants over the course of the pandemic, but only five major variants, affecting large populations of people, received Greek letter designations (Alpha, Beta, Gamma, Delta and Omicron). Each of these previous variants had numerous sub-lineages, or mutations that might be considered relatives of the main variant, but had no functional consequence – they did not increase transmissibility or pathogenicity. But with Omicron, we have already seen multiple subvariants with heightened infectiousness, not just BA.2, BA.2.12.1, but also BA.4 and BA.5 which are leading to a new wave in South Africa.

As we watch the virus strikingly improve its ability to find new or repeat hosts, you would think it would be considered an urgent call for action. But instead, there has been a public perception that the pandemic is over, while, at the same time, public health agencies are adopting the policy that we have to “live with Covid”.

No, we don’t have to live with Covid, because the Covid we are seeing now is deeply concerning. While there has not been a surge in hospitalizations, they are clearly on the increase, with more than a 20% rise in the United States over the past two weeks. The proportion of people getting hospitalized and dying among the vaccinated, as compared with unvaccinated, has substantially increased. As have the deaths: during the Delta wave in the United States, vaccinated individuals accounted for 23% of the deaths, whereas this nearly doubled to 42% during the Omicron wave. Many of these hospitalizations and deaths among vaccinated people can be attributed to lack of a booster shot or the substantially waned effectiveness that sets in by four months after a booster.

Moreover, a major misconception is that the vaccines are holding steady to protect against severe disease, hospitalizations and deaths. They are not. When a booster was given during the Delta wave, that fully restored protection against these outcomes, to the level of 95% effectiveness. But for Omicron, with a booster (or second booster) the protection was approximately 80% – which, while still high, represents a significant, fourfold dropdown (lack of effectiveness of 55% v 20%).

Accordingly, the confidence that our vaccines, created to fight the original strain from 2019, are highly protective against severe illness is exaggerated. No less concerning are the clear signs that the durability of such protection is reduced. All of this is tied to the marked evolution of the virus, and we yet lack any data on vaccine effectiveness against the BA.2.12.1 variant, soon to be dominant here.

With the prospect for more noxious variants that lie ahead, it is unfathomable that we now surrender. No more funding from the government. The only new vaccine in the hopper is an Omicron booster, but since that is based on the BA.1 variant, it may not provide much protection against what we are seeing now (BA.2.1.2.1 has reduced cross-immunity) or where the virus will be come this summer when that vaccine may become available. We even face a shortage of vaccines in the months ahead.

Rather than giving up, it is time to double down on innovations that have high likelihood of anticipating the further evolution of the virus and facilitating the end of the pandemic. First on the list is the development of nasal vaccines that are variant-proof. A nasal spray that induces mucosal immunity would help to block transmission, for which we have minimal defense now from the hyper-transmissible Omicron family of variants. Three such nasal vaccines are in late-stage clinical trials, but unlike the shots, there has not been any Operation Warp Speed or governmental support to expedite their execution or success.

Next, with so many promising candidate drugs, is to speed these clinical trials. Recall that Paxlovid was the most rapid small molecule (pill) program in history, less than two years from design of the molecule to the completion of definitive randomized trials showing high efficacy and commercialization. Why hasn’t such aggressive pursuit been applied to so many other antivirals, which include pills, inhaled nanobodies and decoys?

The concept of a pan-β-coronavirus or pan-sarbecovirus vaccine is alluring and has been pursued by academic labs throughout the world over the past two years. Tens of broad neutralizing antibodies (bnAbs) have been discovered, which have high likelihood of protecting against any future variant. But there is nearly a void of developing and testing a vaccine based on these bnAbs. Such vaccines are clearly in our reach, but the lack of investment in a high priority and velocity initiative is holding us back. A combination of nasal or oral vaccines, more and better drugs, and a variant-proof coronavirus vaccine would catalyze a definitive pandemic exit.

The public perception that our vaccines are “leaky” is true, but it’s off-base to assign the fault to the vaccines, which have saved millions of lives around the world. It’s the virus’s accelerated evolution – its sneakiness and its ability to become more formidable over time – that is at the root of our problem now. We can outsmart and finally get ahead of the virus if we don’t submit to fatigue and to foolishness.

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