BA.4/.5 - The Uninvited Guest at your July 4th Celebration?
Further Information on the Monkey Business
I had been hopeful that the relatively small BA.4/.5 fifth wave of disease in South Africa would portend a similar outcome here in the US, but some data is accumulating suggesting that may be too sanguine a view. It is clear now that Portugal’s current wave of disease, which is the worst in Europe currently, is being driven almost exclusively by the BA.4/.5 Omicron sublineages—accounting for 90% of new infections. Unfortunately, highly vaccinated and boosted Portugal just recorded record hospitalizations, and a close runner up, second highest daily death rate since the peak of Omicron in February. Here in the US, the recent surge in cases, caused by BA.2.12.1, is showing signs of slowing down in the regions where it first exploded (New York, New Jersey, the Northeast and Michigan) but cases are on the rise in the majority of the rest of the country. More importantly, hospitalization totals are continuing to rise.
A logical question would be, if we are now in the midst of a nationwide spike in cases due to BA.2.12.1, why should we worry about yet another son of Omicron? After all, we are vaccinated, boosted, perhaps double boosted, recovered from infection (maybe even with Omicron) so our immune systems should be revved up in high gear to fend off this critter. Unfortunately, recent events are making it clear that we are still in the midst of confronting a rapidly mutating novel virus, which quickly adapts to our changing immunity. We have not yet reached an equilibrium point where the virus has become a relatively predictable endemic pathogen. We are relying on vaccines which have been totally bypassed in terms of ability to prevent infection, while mercifully, if not taken in the too remote past, are still providing a very decent, albeit eroding, buffer against critical illness and death. Only 4-5 weeks ago BA.4/.5 accounted for .02% of US viral sequences. The most recent data shows it at 5-6% of the total. This variant is demonstrating a very short doubling time while competing against the currently dominant Omicron derived BA.2.12.1 and the fading BA.2. Recent history will repeat itself and this variant can be expected to sweep the country in a relatively short time frame.
What of our hard won immunity? The epidemiological data shows that BA.4/.5 caused a moderate 5th wave of cases in South Africa following the huge Omicron peak, and it is causing a very large wave now in Portugal. The immunology data from the lab is confirming the mechanism for this. Last week in preprint, researchers from Dr. David Ho’s laboratory at the Aron Diamond Institute reported on the degree to which BA.4/.5 escapes from neutralization by a large panel of monoclonal antibodies; and more importantly, from the neutralizing capacity of immune sera from people with three doses of mRNA vaccine, as well as people with both vaccination and subsequent Omicron lineage infection.
https://doi.org/10.1101/2022.05.26.493517
There’s a lot of data in the paper, but a very significant finding is that compared to BA.2, the current bad boy BA.2.12.1 sweeping the country is only 1.8 fold less susceptible to boosted vaccine serum, while BA.4/.5 is 4.2 times less neutralized. Further, this new variant was found have a similar level of resistance to sera from boost vaccinated people who experienced a subsequent Omicron lineage infection. I might have lost you or myself by now, but the bottom line is that BA.4/.5 has sufficient antibody escape to have a decent shot at infecting you even if you are boost vaccinated, and even Omicron recovered after that. Factor in the vanishing social mitigation efforts around the country, the desultory governmental approach to encouraging booster doses for the most vulnerable, the phenomena of Paxlovid rebound with the potential to spread the virus after treatment, and the fast approaching season of hot summer weather with people congregating indoors, and it looks like another round of COVID may be on the July 4th invitation list. Personally, I had been very cavalier for a period of time following my own Omicron breakthrough infection after boosted vaccination, feeling that a good deal of protection was afforded by Omicron. The reality is substantially different now. Relatively healthy, vaccinated and boosted younger people don’t need to worry much at all about serious illness and hospitalization, but the experience of the Omicron wave showed us that people with any of the relevant compromising conditions, including simply age > 65 or 70 are still at risk of bad outcomes from the newer variants. It may certainly be the case that we are all destined to catch COVID over and over again, as Katherine Wu’s piece in the May 27th Atlantic suggests, but if you are at higher risk for either acute COVID morbidity, or have concerns about the possibility of Long COVID symptoms, you might want to take some simple precautions right now, while we are still in this period of viral and human mutual adaptation. You know what to do to lessen your risk—as the old saying goes, “You pays your money and you takes your chances.”
A quick update on the Monkey Pox story to close today. In the last post I quickly went over some of the competing theories regarding the likely cause for the sudden Monkey Pox outbreak in multiple countries around the world. As of Friday June 3rd, it looks like there are 25 confirmed cases in the US since the first documented case on May 18th, not exactly a rampaging epidemic. It looks like my hunch was correct that there would be a significant change in the virus to explain both the apparent increase in human transmission, and the unusual clinical pattern being observed. The following two preprints from Portugal appeared several days ago looking at viral sequences from multiple European Monkey Pox patients.
Multi-country outbreak of Monkey Pox virus: Genetic Divergence and First signs of Micro-evolution. Joana Isidro1, Vítor Borges1, Miguel Pinto1, Rita Ferreira1, Daniel Sobral1, Alexandra Nunes1, João Dourado Santos1, Verónica Mixão1, Daniela Santos2, Silvia Duarte2, Luís Vieira2, Maria José Borrego3, Sofia Núncio4, Ana Pelerito4, Rita Cordeiro4, João Paulo Gomes1,*. Genome Reports.
Confirmation of the phylogenetic placement unveiled by the first draft sequence Isidro et al, 235: the outbreak virus belongs to the West African clade and is most closely related to viruses (based on available genome data) associated with the exportation of monkeypox virus from Nigeria to several countries in 2018 and 2019, namely the United Kingdom, Israel and Singapore (1, 2).
Still, the outbreak virus diverges a mean of 50 SNPs from those 2018-2019 viruses (46 SNPs from the closest reference MPXV_UK_P2, MT903344.1) (Table 1_2022-05-23.zip (15.0 KB)), which is far more than one would expect considering the estimated substitution rate for Orthopoxviruses (3).
Their conclusions are that the world wide outbreak most likely had a single source. The virus is most similar to the West African clade, but differs from the more recent members of that family by more base pair mutations than would be expected given the baseline rate of random evolutionary drift in this type of double stranded DNA virus. The current virus has a large genetic deletion, and similar events of gene loss have been associated with increased person to person transmission seen in the more pathogenic Central African clade. The virus is mutating quickly enough to possibly allow them to construct a detailed tree of how the epidemic spread, but that rate of mutation is surprisingly high for this kind of virus. Those with suspicious minds will no doubt find fertile ground here for implicating some clandestine laboratory hanky panky with the virus. Since the chimps and the rope squirrels aren’t giving interviews, I’ll go with the more likely human, monkey, rat interaction that might be hanky, but without the panky.
Thanks for your interest and as always, feel free to share with your friends and colleagues.
Thanks, Dr. Kocher!