Vaccines Driving Evolution of XBB Omicron Is An Interesting But Incomplete Hypothesis


Earlier this year, an opinion article in The Wall Street Journal (WSJ) argued that the Covid-19 vaccines might have been driving the evolution of XBB. 

XBB is the latest successful Omicron subvariant, which has taken hold in numerous countries, including countries with high vaccination and boosting rates. Is there any truth in this hypothesis, though? Let’s evaluate both sides of the argument and see. 

This hypothesis is not new, though. Similar concerns were raised before, usually by the anti-vaccine community. I wrote about this hypothesis back in August 2021. Some of my arguments back then are still relevant, which I’ll repeat in this article. 

The WSJ opinion

The author, Allysia Finley, journalist and member of the WSJ editorial board, began by citing a study that analyzed the evolution of Omicron, which suggested that immune imprinting from the vaccines may have contributed to XBB evolution. 

The study, published in Nature, analyzed the immune evasion abilities and mutational profiles of Omicron variants and subvariants. Among the tested variants, XBB and BQ1.1 exhibited the strongest resistance to monoclonal antibodies and antibodies from vaccinated individuals, while retaining their cell binding efficiency. Such resistance was even comparable to 2002/2003 SARS-CoV-1, showing an immense evolution leap. 

The same study then investigated how XBB evolved. They found evidence of immune imprinting (or original antigenic sin) as early as BA.2 and BA.5 Omicron vaccine-breakthrough cases, where antibodies mainly targeted the original Wuhan variant. Omicron-specific antibodies were rarely present compared to Omicron infection in the unvaccinated. 

Further experiments showed that such non-Omicron-specific antibodies imposed immune pressure to eliminate non-Omicron mutations, resulting in convergent mutations towards and survival of Omicron variants. This explains why Omicron is the dominating variant to this day, because vaccine-induced immunity has eliminated non-Omicron variants. 

Finley also cited two more recent studies showing clinical evidence of immune imprinting from the Covid vaccines (even bivalent ones), where vaccine-induced antibodies were 20–150 times weaker against the XBB variant compared to the original Wuhan variant. 

Moving on, Finsley cited the infamous Cleveland Clinic study showing that the more vaccines taken, the higher the risk of infection (Figure 1). But this data alone can be easily taken out of context. While other studies have also found more Omicron infections from more vaccinations, the risk of severe Covid is still lower with more vaccinations. 

Probable reasons for this discrepancy include behavioral differences (e.g., vaccinated individuals are the ones who are more likely to get infected, such as frontline healthcare workers), IgG4 class switch, and immune imprinting — which I previously covered here
Fig 1. Cumulative incidence of COVID-19 for subjects stratified by the number of COVID-19 vaccine doses previously received.Photo byShrestha et al. (2023).

Finsley then pointed out that early XBB surges appeared in regions with one of the world's highest vaccination and boosting rates, such as Singapore and the Northeast U.S. (New York, New Jersey, Connecticut, and Massachusetts). In contrast, XBB has been slower to take off in the South and Midwest U.S., with comparatively lower vaccination rates. 

“Two years ago, vaccines were helpful in reducing severe illness, particularly among the elderly and those with health risks like diabetes and obesity,” Finley wrote. “But experts refuse to concede that boosters have yielded diminishing benefits and may even have made individuals and the population as a whole more vulnerable to new variants like XBB.”

The crux of Finley’s argument is that immune printing from vaccines imposes a selection pressure that eliminates the old variants and selects for newer variants, leading to global convergent mutations toward Omicron variants and subvariants. This is why XBB and other Omicron variants emerged and surged even in the most vaccinated and boosted regions. 

Finley’s argument adds to the previous anti-vaccine argument of the leaky vaccine hypothesis, infamously popularized by Geert Vanden Bossche, Ph.D., as what will happen with Covid-19 vaccines. In brief, because Covid-19 vaccines aren’t designed to prevent infection and transmission (but to prevent symptomatic and severe disease), vaccines will just select for the survival of more infectious and transmissible variants. 

Let’s see what other experts have to say

Kristen Panthagani, MD, Ph.D., resident and scholar at Yale New Haven Hospital, as well as a science communicator, emphasized that variants come from infections, not vaccinations. 

Dr. Panthagani further stressed that vaccines aren’t like antibiotics that can be easily defeated with antibiotic-resistant bugs. Antibiotics often rely on a single mode of action, whereas vaccines rely on training the entire army of the immune system. Evolving vaccine resistance is thus very unlikely, as unlikely as evolving resistance against multiple antibiotics. 

But multidrug-resistant bugs do exist on a regular basis. As such, vaccine-resistant bugs like the Omicron variant of SARS-CoV-2 also exist. But generally, evolving vaccine resistance is harder than antibiotic resistance because the threshold to overcome a vaccine’s defenses is higher than antibiotic’s (Figure 2). That’s why experts were very confident that the vaccines would curb SARS-CoV-2 evolution.
Fig 2. Vaccine resistance is far less likely to evolve than antimalarial and antibiotic resistance, as evidenced by the length of red line.Photo byKennedy and Read (2018).

Once that threshold is overcome, however, using the same antibiotics will aggravate the state of antibiotic resistance. Likewise, it can be argued the same for using the same vaccines, although not many will agree or admit to this controversial thought. 

But Dr. Panthagani further explained that:

“However, if a new variant arises that has the ability to evade prior immunity (either from vaccines or prior infections), then that variant will spread more easily compared to other variants. This is where people get confused… vaccinated people don’t increase the chance of a vaccine-resistant variant arising, but if a new variant does arise that is (by chance) partially resistant to vaccines, then that variant will spread more easily because it is now (at least partially) dodging people’s immune defenses.”

This is a good point— variants arise from random mutations, regardless of vaccinated or unvaccinated individuals. And it’s ultimately the immunity landscape — whether from vaccination or natural immunity or both — that will determine which variants survive. I’ll explain more about this later. 

Next, writing for Blomberg and The Washington Post, journalist Faye Flam wrote a counter article specifically against the WSJ article. 

According to Jesse Bloom, Ph.D., professor of computational biology, Flam mentioned that XBB.1.5 didn’t actually emerge in the Northeast U.S. with high vaccination rates. Rather XBB.1.5 is the offspring of XBB and XBB.1, which likely originated somewhere in Asia. 

But Asian countries, Singapore included, typically have high vaccination rates, probably influenced by their collectivistic culture. So Flam’s first argument may not do justice in countering Finley’s. 

That said, Flam made the following good point: 

“So, yes, vaccines do put evolutionary pressure on the virus and in that way steer its evolution. But it’s misleading to suggest that vaccines are making our situation worse — without them, we’d still see immune-evading variants, and those infections would be causing more deaths.

Flam then cited the study of Roby Bhattacharyya, MD, Ph.D., assistant professor of medicine at Massachusetts General Hospital, and colleagues showing that population immunity has no impact on the rate of Delta or Omicron dominance over prior variants. This means that the emergence of SARS-CoV-2 variants of concern likely has little to do with vaccination rates — that they dominate regardless of high or low vaccination rates. 

In other words, if Omicron variants would dominate regardless of vaccination rates, vaccines should not be blamed. And without vaccines, more Covid deaths would’ve befallen us. 

So, is the WSJ hypothesis valid?

The short answer is it’s partly valid, although some may disagree.

Darwinian evolution depends on two basic factors: random mutations and natural selection pressure. Genetic mutations arise randomly, which may improve, weaken, or do nothing to the organism’s fitness to survive in the environment. Nature (in this case, vaccination) then imposes selection pressure that favors the proliferation of beneficial mutations.

In the random mutational context, vaccines are not to be blamed for the emergence of Omicron variants. Because mutations that produce such variants arise randomly — in vaccinated or unvaccinated groups alike — due to imperfect genetic replication, which comes with errors (mutations) with each round of virus replication.*

*Previous data showed that vaccination reduces the frequency of random mutation in the Delta variant of SARS-CoV-2. But with more immune-evasive Omicron, things have changed, and vaccines and boosters don’t protect against infection as well due to reasons such as immune imprinting, as Finley from WSJ argued. But vaccination still protects against severe disease, even from Omicron. 

But did the vaccines promote the survival of such variants? Yes, because vaccines impose a selection pressure that only allows the survival of vaccine-resistant variants. In this sense, the vaccines or, more accurately, population immunity, may be responsible for the further selection of vaccine-resistant or immune-evasive variants. Notably, the same selection pressure also applies to immunity from natural infection, so it may be unfair to put the blame solely on vaccines. 

I used the word may as this is not proven for Covid vaccines. The work of Dr. Bhattacharyya et al., for instance, suggests that Omicron dominance had little to do with vaccination rates, so the jury is still out on how much of a role Covid vaccines or natural immunity play in the evolution of XBB. 

So, depending on how you look at the situation — from the random mutation or selection pressure viewpoint — vaccines may not be truly innocent, but vaccines are not to be held 100% accountable either.

Ultimately, vaccines are just one of our tools to fight pathogens, but pathogens can also fight back — it’s an evolutionary arms race that won’t end unless the virus or pathogen is eradicated. 

Some anti-vaccine views have simply overestimated the effects of the latter (pathogens evolving vaccine resistance), underestimated the former (the benefits of vaccination), and blamed the vaccines. But in reality, the relationship between vaccines and virus evolution is not so simple that we can arrive at a conclusion easily.

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MSc Biology | 8x first-author academic papers | 280+ articles on coronavirus | Independent science writer


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