A comprehensive overview of what’s happening and what might happen as we face the evolving coronavirus.
A thought came to my mind: What if a population of unvaccinated and vaccinated hosts creates a selection pressure that selects for the evolution of more dangerous variants than Delta? Let’s take a critical look at whether this concern is justified and see what’s happening and what might happen as we engage in an evolutionary arms race with SARS-CoV-2.
(Note: variants mentioned herein belong to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Covid-19.)
Delta’s current data
Following the World Health Organization’s (WHO) new naming system, the variant under the lineage B.1.617.2 — first discovered in India in December 2020 — is called Delta. Delta has several mutations in its spike protein that endow it with abilities to bind to cells and evade the immune system’s antibodies much more efficiently.
I. More infectious and transmissible
Delta is 40–60% more transmissible than Alpha, a rapidly spreading variant first noted in the U.K. that’s already 50–70% more transmissible than the original variant in Wuhan in December 2019. This means that Delta spreads at least twice as fast as the original variant. The Centers for Disease Control and Prevention (CDC) has estimated that Delta is more contagious than Ebola and smallpox and as contagious as chickenpox.
An unpublished study from China found that people infected with Delta produced 1260-times more viral load and tested positive sooner (4 vs. 6 days) than people infected with pre-Delta variants. So, the faster infection (leading to sooner positive tests) and replication (higher viral load) do indeed make Delta highly transmissible.
II. More vaccine-resistant
Most studies showed that Delta is partially vaccine-resistant. But thankfully, the vaccines (full dose) still protect against severe Covid-19 leading to hospitalization and death from Delta. For Delta infection and symptomatic Covid-19 (usually non-severe), however, the vaccines are no longer as effective as before.
- England’s published data: Pfizer and AstraZeneca vaccines prevented 88% and 67% of symptomatic Covid-19, respectively, that Delta caused. These numbers are 94% and 75%, respectively, for the Alpha variant. If it’s only one dose of either Pfizer or AstraZeneca, the efficacy is just 30% against Delta and 50% against Alpha.
- Scotland’s published data: Pfizer vaccine prevented 79% and AstraZeneca vaccine prevented 60% of Delta infections. These figures are 92% and 73%, respectively, for the Alpha variant.
- Canada’s unpublished data: Pfizer vaccine prevented 87%, 89%, and 84% of symptomatic Covid-19 cases from Delta, Alpha, and Beta/Gamma variants of concern, respectively. So, the vaccines don’t seem to lose their efficacy against Delta in this study. (Beta and Gamma, first identified in South Africa and Brazil, harbors mutations that make them more antibody-resistant than Alpha.)
- Israel’s unpublished data: Pfizer vaccine reduced the risk of severe Covid-19 by 91%, transmission by 89%, hospitalization by 88%, symptomatic Covid-19 by 40%, and infection by 39%. (But there’s a concern that the 39% figure may be an underestimate.) Before Delta’s dominance, such numbers were 95% for symptomatic Covid-19 and close to 100% for severe Covid-19. (Note that these numbers are relative risks, where the risk of x in the vaccinated group is compared to the risk of x in the unvaccinated group. So, the above points provide numbers that are easier to understand than Israel’s data.)
- Other data showed that antibodies isolated from persons vaccinated with Moderna, Pfizer, or Johnson & Johnson vaccines or unvaccinated persons with natural immunity were 2–7-times weaker against Delta. But how lab experiments translate to public health is not always apparent.
III. More severe
A third problem Delta brings is possibly more severe Covid-19.
- Scotland’s published data: Persons infected with Delta had an 85% increased risk of hospitalization compared to Alpha.
- Canada’s unpublished data: Persons infected with Delta had 108%, 234%, and 132% increased risks of hospitalization, ICU admission, and death, respectively, compared to non-variants of concern. For N501Y-positive variants (such as Beta and Gamma variants of concern), these numbers were 52%, 89%, and 51%, respectively.
- Singapore’s unpublished data: Persons infected with Delta had a 390% increased risk of oxygen requirement, ICU admission, or death compared to pre-Delta variants.
But whether Delta is actually deadlier is inconclusive. We can’t prove causation from observational studies. Only randomized controlled trials can prove causation, but we can’t deliberately infect people with Delta.
One reason for the increased risks of severe Covid-19 from Delta might be that Delta is too contagious, leading to more infections that, in turn, lead to more severe cases among vulnerable groups — such as older persons and those with multiple comorbidities or unvaccinated. In other words, more infections could reach the high-risk groups more often.
For these reasons, the U.S. CDC has re-emphasized the necessity of masks even in fully vaccinated people, especially indoors, to curb Delta’s spread. The WHO has even called Delta “the most able and fastest and fittest of those viruses.”
Delta could breed more dangerous variants
Based on the bulleted points above, vaccines only reduce the risks of Delta infection but do not stop it. As also mentioned, unvaccinated persons with Delta infection could carry a 1260-times greater viral load than usual.
More worryingly, one unpublished study from India and the U.K. found that Delta viral loads were only slightly lower in vaccinated (with AstraZeneca) than unvaccinated persons. Two more studies from the U.S. — one published and one unpublished — reported similar viral loads between vaccinated and unvaccinated persons infected with Delta.
Importantly, another unpublished study from Singapore found that Delta viral loads were similar among vaccinated (with Pfizer) and unvaccinated persons initially, but the viral load dropped faster in the vaccinated group. This finding suggests that vaccines could reduce the duration of being in a contagious state to some extent.
Another worrying problem is that ongoing Delta infection and transmission in a population of vaccinated and unvaccinated hosts may allow evolution to give rise to something more notorious.
In a newly published study, European researchers used mathematical modeling to predict the trajectory of SARS-CoV-2 vaccine resistance. The model showed that mass and rapid vaccination would discourage the emergence of new vaccine-resistant variants. But if we fail to reach sufficient herd immunity — even with a good amount of vaccine coverage — the risk of vaccine-resistant variants emerging is high within the next three years. The estimated threshold for this is 60% vaccine coverage, where new vaccine-resistant variants will most likely occur. A 60% or less vaccine coverage is where most parts of the world currently stand.
“What our model showed is that when most people are vaccinated, the vaccine-resistant strain has an advantage over the original strain,” Simon A. Rella, a researcher at the Institute of Science and Technology Austria and the study’s lead author, told reporters. “This means that the vaccine-resistant strain spreads through the population faster than the original strain at a time when most people are vaccinated.”
“Generally, the more people are infected, the more the chances for vaccine resistance to emerge. So the more Delta is infectious, the more reason for concern,” Fyodor A. Kondrashov, professor of evolutionary genomics and the study’s director, added. “By having a situation where you vaccinate everybody, a vaccine-resistant mutant actually gains a selective advantage.”
Other researchers who have read the modeling study cautioned that models only predict something, providing an early warning for us to act. But they also said that the modeling study is robust, reasonable, and intuitive as the results are consistent with how the evolution of vaccine resistance works. For example, one of them said:
In essence, viral infection and transmission in a mixed population of vaccinated and unvaccinated hosts would create selection pressure. In response to this pressure, the vaccine-prone variants will gradually die, and vaccine-resistant variants will survive, adapt, and proliferate in an evolutionary process called natural selection. In essence, SARS-CoV-2 will try harder to infect vaccinated hosts.
Does this mean that vaccines would make things worse? Possibly, but vaccines are not at fault:
- If SARS-CoV-2 transmission is kept low — via sufficiently high vaccine coverage and widespread masking and physical distancing — viral evolution would be suppressed.
- If SARS-CoV-2 transmission remains high —due to imperfect vaccine efficacy, lack of masking and physical distancing, and a high prevalence of unvaccinated hosts — viral evolution would be accelerated.
The recent appearance of the Delta plus variant (also called B.1.617.2.1 or AY.1.) in Europe in March 2021 shows that Delta could still evolve. Delta plus has also spread to other countries, including the U.S., India, and South Korea. Compared to Delta, Delta plus has acquired a few more mutations — notably K417N that’s also found in Beta and Gamma variants of concern. But whether Delta plus is more transmissible, vaccine-resistant, or severe is still unclear. After all, more mutations aren't necessarily good as mutations can either be neutral, beneficial, or harmful for the virus’s fitness.
Lambda has Delta’s potential
First discovered in Peru in August 2020, the Lambda (C.27 lineage) variant has spread to at least 29 countries, especially South America. Lambda now causes over 80% of SARS-CoV-2 cases in Peru, a country with the highest Covid-19 mortality rate worldwide.
The WHO still considers Lambda a variant of interest — a stage below a variant of concern such as Alpha, Beta, Gamma, and Delta. The CDC, however, has not listed Lambda as a variant of interest or concern, so Lambda doesn’t seem to cause trouble in the U.S. for now. In the U.S., less than 1% of sequenced SARS-CoV-2 samples were Lambda, but note that the U.S. only sequenced about 1.4% of SARS-CoV-2 samples.
A recent unpublished study from Japan showed that Lambda is 50% more resistant than usual to antibodies isolated from persons fully vaccinated with Pfizer. This study also found mutations in Lambda‘s spike protein that enable it to infect cells nearly as easily as Delta (see figure below).
Further analyses showed that such vaccine resistance and cell infectiousness are mostly attributed to the L452R/Q mutation that Lambda and Delta share. In this Japanese study, not even Alpha, Beta, and Gamma were as infectious as Lambda and Delta.
Another unpublished study from New York also revealed that Lambda was as infectious and vaccine-resistant as Delta and Delta plus. Specifically, the vaccine-elicited antibodies were 3.6-times (Moderna), 3.2-times (Pfizer), and 6.1-times (J&J) less effective at neutralizing Lambda than earlier variants.
But laboratory data like these may or may not translate to real-world situations influenced by human actions and other factors. So, it’s best not to conclude anything about Lambda yet. Still, such laboratory data tells us to watch out for Lambda.
All that said, Lambda is another sign that SARS-CoV-2 is evolving. If Delta did not arise or dominate some parts of the world, Lambda might have taken over, like what’s happening in Peru. This also raises the possibility that Lambda (or other variants) might take over if Delta is successfully controlled (such as via vaccine boosters). Although Lambda and Delta share the L452R/Q mutation, they belong to different sublineages and own different mutations, making them rather evolutionary distant.
How will things play out?
Delta, Delta plus, Lambda, and possibly other variants in the future tell us one thing: the Covid-19 pandemic is far from over. With the unequal global vaccine distribution, vaccine hesitancy and distrust, and public health blunders, we have missed our chance to end the pandemic.
Vaccines are still our best weapon, though. Recall that the vaccines are still highly effective at preventing severe Covid-19 from Delta. Based on the U.S. data, amidst Delta’s dominance, the risks of hospitalization and death are 25-times lower in fully vaccinated versus unvaccinated persons (see figure below). Specifically, based on the current incidence of 35,000 symptomatic Covid-19 cases per week, 2.52 per 100,000 unvaccinated persons got hospitalized, whereas this number was only 0.1 per 100,000 for fully vaccinated persons, giving a 25-times risk reduction.
Thus, at least for now, fully vaccinated persons have less to worry about.
But it might be a matter of time before something worse than Delta evolves (as discussed earlier). This is also one reason why some countries are considering or are implementing mask or vaccine mandates, travel restrictions, and booster shots for high-risk groups: adults who are older, immunocompromised, or have underlying medical conditions.
The WHO, however, has pleaded to delay giving booster shots until other countries with low vaccine coverage are helped. Examples include India, Indonesia, and South America, where less than 10% of the population is fully vaccinated as of August 2021. It’s indeed hard to justify boosting the protection of people who already have some protection when others are still vulnerable.
“We cannot and should not accept countries that have already used most of the global supply of vaccines using even more of it while the world’s most vulnerable people remain unprotected,” Dr. Tedros Adhanom Ghebreyesus, director-general of the WHO, said this week.
Booster shots are also not a guaranteed solution. Who knows if boosters won’t be as effective against Delta or Delta plus as we hope; who knows if Lambda might not take over Delta; who knows if another variant won’t emerge by then, especially when many countries still have a low vaccine coverage; who knows if the original antigenic sin won’t happen.
(Original antigenic sin occurs when old immunity is prioritized over a new one. So sometimes, vaccine boosters strengthen existing immunity against the old version of a pathogen rather than helping the immune system make new immunity against the new version. Original antigenic sin is one reason why it’s difficult to create highly effective seasonal influenza vaccines.)
Despite these uncertainties, sometimes we have to try. Boosters will really be necessary when the time comes that vaccines’ efficacy against severe Covid-19 declines drastically. For now, to reiterate a crucial point, the vaccines are still very powerful at preventing severe Covid-19.
All that said, the best moral act now is to curb SARS-CoV-2 infection and transmission as much as possible. That means getting fully vaccinated (if haven’t) and be more careful indoors, especially in places with poor ventilation by wearing a mask and distancing. Lockdowns might also be an option, although this is the government’s decision that we can’t do much about on the individual level; plus, lockdowns aren’t risk-free either.
But masks, distancing, and improving indoor ventilation are risk-free, and vaccines aren’t as risky as someone might think. One can only imagine how much worse the Delta situation would have been if current Covid-19 vaccines didn’t exist. At least we can be thankful that vaccines have put us one step forward against the evolving coronavirus.
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