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The Covid Capitulation
As the virus accelerates its evolution, humans retrogress
The United States is now in the midst of a new wave related to Omicron variants BA.2 and BA.2.12.1 with over 90,000 confirmed new cases a day and a 20% increase in hospitalizations in the past 2 weeks. That belies the real toll of the current wave, since most people with symptoms are testing at home or not testing at all; there is essentially no testing for asymptomatic cases. The real number of cases is likely at least 500,000 per day, far greater than any of the US prior waves except Omicron. The bunk that cases are not important is preposterous. They are infections that beget more cases, they beget Long Covid, they beget sickness, hospitalizations and deaths. They are also the underpinning of new variants.
Meanwhile, the CDC propagates delusional thinking that community levels are very low (as my friend Peter Hotez called the “field of greens”) while the real and important data convey that transmission is very high throughout most of the country. Not only does this further beget cases by instilling false confidence, but it is conveniently feeding the myth that the pandemic is over—precisely what everyone wants to believe.
As of last week, 43% of new cases were attributable to BA.2.12.1 and this subvariant had reached dominance (>50% of cases) in only one region of the country. BA.2.12.1 is out-competing BA.2 with its 25% higher transmission rate, which foretells its further rise to dominance across the US in the days and weeks ahead.
Why is the transition to BA.2.12.1 important?
BA.2.12.1 is quite distinct from Omicron BA.1 and BA.2. As you can see on this mutation map of the spike, which is just one part of the virus sequence, albeit a critical one, there is a key, unique mutation L452Q. The other important Omicron subvariants currently, BA.4 and BA.5, have multiple different mutations (including L452R, F486V and R493Q) from BA.2, and account for the new wave of cases in South Africa, and more recently in Portugal, and have just been labelled as VoC (variants of concern) by the European Centre for Disease Prevention and Control. Both BA.2.12.1 and BA.4/BA.5 pose a further challenge to our immune system recognition, with minimal cross-immunity derived from BA.1. That is especially noteworthy since 40-50% of Americans were infected with BA.1 (or BA.1.1) and without added protection from vaccination, they will be vulnerable to BA.2.12.1 infections. It is further worth mentioning that the Omicron-specific booster vaccines in the hopper, thought to be due out in July, are BA.1 directed and may not provide strong protection against BA.2.12.1 or whatever new Omicron subvariant (or not Omicron related) we will be dealing with this summer. It remains to be seen whether BA.4/BA.5 can outcompete BA.2.12.1, with the former now at low levels in the US.
It’s not just about the mutations, immune escape, and potential of Omicron BA..1 vaccines (that have taken far too long) to be unhelpful. There are 2 other essential points. First, this family of Omicron variants with functional impact indicates more rapid evolution of the virus than what we have seen previously. Very few of the thousands of variants since late 2019 have led to significant spikes of cases around the world—only 4 (Alpha, Beta, Gamma, and Delta) before Omicron. But now multiple Omicron subvariants are outcompeting one another, predominantly because of more immune evasion, such that BA.2 with 30% more transmission overtook BA.1, and BA.2.12.1 (in parallel to BA.4 and BA.5) has a substantial transmission advantage over BA.2. To put this in context, Dr. Linfa Wang recently opined: "Based on its immunological profile, it should be called SARS-3".
Second, it is about the reduction in vaccine effectiveness that we are now encountering. Obviously, a breakdown of protection from transmission occurred with Omicron with “breakthroughs” in people with vaccination occurring quite commonly. That, and reinfections, were an unusual phenomenon (~1%) before Omicron. Now we are seeing people with 4 shots who are getting breakthrough infections, even at 1-2 weeks from their most recent shot, when there should be the maximal level of neutralizing antibodies induced. That’s not a good sign, relative to the 95% vaccine effectiveness we had against symptomatic infections against the ancestral, D614G, Alpha, and Delta (with a booster) strains.
But it’s worse than that. Because we have relied (and taken for granted) on vaccines to protect us from severe disease—to prevent hospitalizations and deaths. Prior to Omicron we could, with a booster, assume there was well over 90-95% vaccine effectiveness vs severe disease. It is clear, however, from multiple reports, including the UK Health Security Agency and Kaiser Permanente that this level of protection has declined to approximately 80%, particularly taking account the more rapid waning than previously seen. That represents a substantial drop-off: instead of a gap or “leak” of 5%, it is about 4-fold at 20%. And we don’t yet know how well vaccines are still holding up with the BA.2.12.2 and BA.4/BA.5 variants. Likely similar to BA.1 and BA.2 because we haven’t seen substantial increases in hospitalizations, but no data are yet available and it’s still early. Certainly those without vaccination, relying on infection-acquired immunity, and at advanced age, are at considerable risk for the Omicron subvariants because their prior exposure only led to narrow (BA.1) protection.
But it’s overly optimistic to think we’ll be done when Omicron variants run their course. Not only are they providing further seeding grounds for more variants of concern, but that path is further facilitated by tens of millions of immunocompromised people around the world, multiple and massive animal reservoirs, and increased frequency of recombinants—the hybrid versions of the virus that we are seeing from co-infections. As difficult it is to mentally confront, we must plan on something worse than Omicron in the months ahead.
To recap, we have a highly unfavorable picture of: (1) accelerated evolution of the virus; (2) increased immune escape of new variants; (2) progressively higher transmissibility and infectiousness; (4) substantially less protection from transmission by vaccines and boosters; (5) some reduction on vaccine/booster protection against hospitalization and death; (6) high vulnerability from infection-acquired immunity only; and (7) likelihood of more noxious new variants in the months ahead
A Delusional Congress
With that handwriting on the wall, how could our government legislators turn their backs on funding critical initiatives to get us through the pandemic? This is frankly absurd, staring at millions of more Americans to get infected that is happening right now (no less the Biden administration has projected 100 million this fall/early winter) that will translate to an unknown number of more hospitalizations and deaths. Ironically, the same administration, via the CDC, is downplaying the risk of our current Covid wave as reviewed above. And this is all happening when we just crossed the 1 million confirmed American deaths (far more via excess mortality), with at least a few hundred thousand of these preventable with vaccines and boosters. You just have to look at these Figures from KFF to see that even people with boosters were succumbing at the start of the Omicron wave (January 2022).
During the Delta wave in the United States, vaccinated individuals accounted for 23 per cent of the deaths, whereas this nearly doubled to 42 per cent during the Omicron wave. This is attributable to waning of protection, lack of boosters, and the diminished protection against Omicron (BA.1).
We’re not just looking at running out of vaccines and antiviral medications. Congress should immediately allocate for an Operation Warp Speed (OWS)-like initiative to bring nasal vaccines over the goal line. Three of these are in late stage clinical trials and success of any would markedly ameliorate our problems of transmission, no less the alluring aspect of achieving mucosal immunity and being variant-proof. That brings us to catalyzing the efforts for a pan-β-coronavirus vaccine, previously reviewed, now that we have discovered tens of broad neutralizing antibodies but have limited traction of these in the form of advanced clinical trials. Our backstop to infections in people at increased risk has turned to Paxlovid, which is increasingly being recognized to have a liability of rebound with infectiousness in many people after the 5-day blister pill pack. Not only does this unanticipated problem urgently need to be sorted out, but we may confront mounting resistance to Paxlovid in the months ahead as its continues to gain wide scale use, and that phenomena that has already been recognized in selected cases after remdesivir treatment. Look at how the evolution of the virus has blown through most of the monoclonal antibodies that were previously highly effective. We urgently need more safe and effective medications, preferably pills, easily administered shots (subcutaneously, not intravenous or intramuscular), or inhalation treatments. There are so many promising ones in the pipeline, yet little to no support to accelerate their progress. Ignoring all these vital needs surely represents Covid capitulation.
From Zero Covid to Zero Covid Deaths
While the policy of zero Covid is untenable with Omicron, as we’ve seen abandoned in many countries such as New Zealand, Australia, and Taiwan, we should adopt the new policy of Zero Covid Deaths. This is diametrically opposed to Covid capitulation. This builds, in part, on the tools that we already have, knowing that the vast majority of deaths occur in people age 60 plus (92% of US hospitalizations have been in people age 50+). All such people need to have vaccination and booster coverage but our CDC has failed to convey their life-saving impact from the get go, a veritable booster botch job as recently reviewed by Kaiser Health News. That’s why we have 31% of Americans who had had 1 booster shot whereas most peer countries are double that proportion. And why we rank 60th in the world’s countries for boosters, and especially poorly among older Americans compared (<65%, age 60+) with many Western Europe and Asian Pacific countries (~85-90%). That doesn't even speak to the need for a 4th dose in this high-risk group or that lack of intensive monitoring of our 7 million immunocompromised people who are not getting help to guide their protection with assay of neutralizing antibodies, or receiving Evusheld monoclonal antibody preventive protection. But well beyond the use of boosters and vaccines, and easy, rapid access to Paxlovid, we absolutely need an aggressive stance to get ahead of the virus—for the first time since the pandemic began—instead of surrendering. That means setting priorities, funding, and the realization, unfortunately, that the pandemic is far from over. Our Covid vaccines and medications are an order of magnitude more effective than what we have for influenza, but even our current level of deaths (we have already had over 175,000 Covid deaths in 2022), no less what may be in store, is still >10-fold in excess of seasonal flu (about 30,000 per year). That is totally unacceptable, nearly totally preventable loss of lives at scale.
No, we don’t have to “live with it” as it currently hurts us.
Humans naturally get tired, but they shouldn’t be foolish or outsmarted by a virus.