It's the virus, stupid.
When the vaccines were first introduced in December 2020, the virus they were designed against was altogether different from what it is today. SARS-CoV-2 had little substantive functional evolution from late 2019 until we saw the Alpha variant spread in the first months of 2021. It was, in retrospect, an easy target with a fraction of the immune escape and transmissibility that we are dealing with now. Had the virus not subsequently evolved so profoundly, its containment would have been straightforward and we wouldn’t be talking about a pandemic right now in the present tense. Breakthrough and reinfections wouldn’t be commonplace. Population-level (“herd”) immunity would have been possible. The 95% efficacy of the mRNA vaccines against symptomatic infections, hospitalizations and deaths, exhibited waning in latter half of 2021, during the Delta wave, but was fully restored with a 3rd shot. Reinfections were less than 1%. We were prevailing over the virus.
But then came Omicron and a s-storm of subvariants that has followed, culminating in the present one—BA.5—with the highest fitness, growth advantage, and immune evasion since the pandemic began. That has been accompanied by the most reinfections seen to date, and, in places like Japan, with excellent vaccination uptake but relatively low levels of prior infection, a monstrous wave of infections that already exceeds Omicron BA.1. During their BA.5 waves, New Zealand currently has the highest deaths per capita in the world (exceeding its BA.1 wave), Australia’s fatalities have risen sharply, as has Israel’s.
Hospitalizations have risen substantially in many countries throughout Europe and the Asian-Pacific during the BA.5 wave, as seen in this graph from Australia (via Ian McKay)
And here in Europe, which, fortunately, is starting to turnaround in the UK and some other countries.
Why are so many infections and reinfections, and a rise in hospitalizations and deaths (albeit not to the extreme levels as Omicron BA.1 in most places or anywhere close) happening with immunity walls (from vaccination, boosters, infections, and their combinations) that have been built to a varying extent around the world?
Let’s review the multiple lines of defense of our immune system (as virologist Jeremy Kamil aptly put it in the NY Times, “this is not our immune systems’ first rodeo”). Here is an over-simplified version of the multi-layered immune response to the virus with our innate, humoral and cellular lines of defense.
As the virus evolved, it has progressively pierced through the first 2 lines of defense, as recently shown with innate immunity interferons inhibited by Omicron, and particularly with BA.5, and the impaired neutralizing antibody response to BA.5 from prior vaccinations/boosters or infections.
While these are not “all or none” phenomenon, the 3rd line of defense is the backup and although it takes more time for T cells to kick in, that is the layer apparently providing a solid, maintained protection from death, far less affected by the variant escape efforts.
Indeed, in 2021 more than 20 million deaths were prevented by vaccines as shown below and vaccines are substantially adding to that life-saving capacity in 2022.
But cellular immunity isn’t the fast immediate response we need, and neutralizing antibodies at high levels appears to be an important part of maintaining a very high protection from death. That appears to be why multiple studies show enhanced reduction of death with a 4th shot (second booster) in people age 50 or higher (an age cutoff used to partition risk of fatality). A 4th shot in this group from US data through the BA.2.12.1 wave had a 96% reduction of death, whereas a 3rd shot was 87% protective, a ~4-fold difference
But let me emphasize: the culprit in all of this isn’t our vaccines, which are now providing little to no protection against infections and transmission. They are damn leaky, which only arose from the emergence of Omicron and has gotten progressively worse as we moved to BA.5 . It’s the virus. That’s why we’ve started to see a crack in protection vs. severe disease from vaccines with boosters, as I previously reviewed (boiling frog metaphor). It’s that we have not gotten ahead of the immune escape properties of virus with a bolstered mucosal immunity strategy—local IgA, neutralizing antibodies in the upper airway—via nasal or oral vaccines to solidify our 2nd layer of defense. Or inhaled interferons to jack up our first line of defense. Or developing a variant-proof vaccine.
As anyone who follows me on twitter knows I have been very critical of the CDC, White House, and FDA for their management of the pandemic.
But to pin the deaths on the current administration, such as below, solely on the basis of poor management, is off-base. It’s primarily that the virus had been morphing to far more challenging versions. Poor management and full reliance on the original vaccine success (“vaccine only strategy”) are certainly contributing factors.
As Akiko Iwasaki and I wrote last week, it is imperative that we launch a new, major initiative, as we called it Operation Nasal Vaccine, to get ahead of the virus and promote respiratory mucosal immunity.
To summarize a few key points:
There is little to no respiratory mucosal immunity from mRNA vaccines in people vs Omicron
Nasal vaccines in animal models induce very high levels of neutralizing antibodies vs Omicron
There are 12 nasal vaccines in clinical trials and 4 are late-stage, Phase 3 but there is no government plan for manufacturing, distribution or regulatory review as there was for the original vaccines.
While only 1 nasal spray vaccine is currently available (FluMist for influenza) we have already had marked success on a comparative basis against SAR-CoV-2 for vaccine efficacy and an oral antiviral pill (Paxlovid vs Tamiflu). Furthermore, the biology of the SARS-CoV-2 virus makes it a more favorable target than influenza
Next week the White House is having a next-generation summit meeting to ponder plans for a nasal and universal, variant-proof vaccines. We’ve had enough of pondering……we need action. Let’s hope we finally get the vital support we need to build on our early and momentous success against the virus. It’s still evolving and we are getting further and further behind. We can do this.