To answer this, we have to understand how viral evolution works in response to selection pressure.
There’s an uncanny observation that the SARS-CoV-2 variants of concern (VOCs)— Alpha, Beta, Gamma, and Delta — arose soon after the vaccine clinical trials in the same countries. As a result, some have speculated that the trials instigated the evolution of those VOCs. Let’s see if they have a point.
Variants of concern (VOCs) emergence and vaccine clinical trials
The World Health Organization (WHO) defines VOCs as mutated SARS-CoV-2 that has one or more of the following features: (i) more transmissible, (ii) more virulent that causes more severe disease, or (iii) more problematic in terms of making public health measures— such as diagnostic tests, drugs, or vaccines — less effective.
(SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, is what causes the coronavirus disease 2019, Covid-19. For simplicity, all variants, including VOCs, mentioned hereon belong to SARS-CoV-2.)
At present, four VOCs exist:
- Alpha (lineage B.1.1.7) emerged in the U.K. around November 2020. It’s 40–70% more transmissible than pre-Alpha variants owing to the N501Y mutation. After a few months, some Alphas have also gained the E484K mutation, making them more virulent and vaccine-resistant. (To read mutational codes, N501Y, for example, means that the amino acid N at position 501 of the SARS-CoV-2’s genome mutated to Y.)
- Beta (lineage B.1.351) emerged in South Africa around October 2020. The N501Y, K417N, and E484K mutations, among others, make Beta more transmissible and vaccine-resistant. Studies have shown that vaccine-derived antibodies were less effective at neutralizing Beta. The AstraZeneca DNA vaccine has even lost its efficacy against Beta entirely in humans, where rates of Covid-19 were nearly identical between fully vaccinated and placebo groups.
- Gamma (lineage B.220.127.116.11 or P.1) emerged in Brazil around December 2020. It has mutations similar to Beta — including N501Y, E484K, and K417N — that make Gamma more transmissible, vaccine-resistant, and virulent. In Brazil, Gamma infections were 1.2–1.9-times more likely to cause death than pre-Gamma infections.
- Delta (lineage B.1.617.2) emerged in India around December 2020. It has multiple unique mutations — notably, T478K, P681R, and L452R — that enhance Delta’s transmissibility, vaccine resistance, and virulence. Delta is arguably the most concerning variant to date, which has spread far and wide in many countries, replacing other VOCs and causing another wave of Covid-19. Delta is also responsible for most of the current vaccine breakthrough infections.
Strangely, the emergence of these four VOCs overlap with the Covid-19 vaccine clinical trials’ period and geographical region:
- AstraZeneca and Oxford performed clinical trials in the U.K., South Africa, and Brazil for the DNA vaccine (adenoviral-vectored) from April 23 to November 4, 2020.
- Novavax conducted the recombinant nanoparticle vaccine clinical trial in the U.K. starting from September 28, 2020.
- Pfizer and BioNTech led a clinical trial across 150 sites — 130 in the U.S. and the rest in Turkey, Germany, Argentina, South Africa, and Brazil— for the mRNA vaccine from July 27 to November 14, 2020.
- Johnson & Johnson did the DNA vaccine (adenoviral-vectored) clinical trial in Argentina, Chile, Colombia, Mexico, Peru, South Africa, Brazil, and the U.S. from 21 September 2020 to 22 January 2021.
- At least six different vaccine clinical trials — Covaxin inactivated, RBD219-N1 recombinant protein, ZyCoV-D DNA, Covishield (AstraZeneca), BBV152 (unnamed) inactivated, and Sputnik V DNA vaccine— were conducted in India, starting from July or October 2020:
* Source: Kumar et al. (2021). “Strategy for COVID-19 vaccination in India.” NPJ Vaccines.
The “imperfect-vaccine hypothesis”
Others have pointed out that the temporal (time) and geographical overlaps between vaccine clinical trials and VOCs’ emergence implies a causal factor — that the trials were responsible for those VOCs. They have pushed forward the “imperfect-vaccine hypothesis” or “leaky vaccine hypothesis” to justify that.
According to this hypothesis, vaccines that still allow infection and transmission will only create a selection pressure that selects for more transmissible pathogens. This won’t happen if the vaccine provides sterilizing immunity, a type of immunity that stops infections. At least for viruses, no infection means no chance of evolution and transmission.
But Covid-19 vaccines were not designed to provide sterilizing immunity, which is why the clinical trials measured the Covid-19 vaccine’s efficacy against symptomatic disease, not infection.
Achieving sterilizing immunity is no easy feat, which requires mucosal immunity. Mucosa means mucous membranes that line the body’s organs, tissues, and cavities. Most vaccines are delivered via injection, which may not elicit enough antibodies dedicated to a specific organ. To this end, intranasal vaccines are being studied, which hopefully can generate more specific immunity to the respiratory tract.
In the absence of sterilizing immunity, mutations will still occur randomly in vaccinated hosts who are infected — akin to unvaccinated hosts — but in lower frequency and higher selection pressure for vaccine-resistant mutants. If such mutants spread to unvaccinated hosts, their untrained immune system will enable higher viral replication, further proliferating such mutants.
The opposite pattern can also occur, where high viral replication in unvaccinated hosts produced vaccine-resistant mutants at random that survive better amidst a population of vaccinated hosts. The vaccine-prone mutants, in contrast, will then gradually wane in number.
Therefore, if SARS-CoV-2 transmission remains high in a mixed population of vaccinated and unvaccinated hosts, the risks of new vaccine-resistant VOCs arising again are very high, as I further elaborated here.
Plus, vaccine resistance is a worrying trait. Vaccine-resistant mutants tend to be more transmissible and virulent since such mutants are better apt at overcoming the immune system‘s barriers and defenses. Breaching immune barriers means a higher chance of infection, and breaching defenses means a higher chance of disease progression into a more severe state.
So, one infamous anti-vaccine view is that mass vaccination with imperfect vaccines amidst a pandemic of highly transmissible SARS-CoV-2 will backfire, such as when the VOCs emerge soon after the initiation and within the proximity of vaccine clinical trials. Really?
Mutation frequency and selection pressure
While the “imperfect-vaccine hypothesis” is a legitimate concern, it’s not everything, and there are other factors to consider.
Let’s take Covid-19 vaccines as examples. Even if they can’t fully prevent infection and transmission, they still suppress viral replication. After all, imperfect vaccines still train the immune system to some extent.
Thus, despite being infected with SARS-CoV-2, the risks of hospitalization and death are 25-fold lower in vaccinated than in unvaccinated persons. This is also why SARS-CoV-2 viral load tends to drop faster in vaccinated than unvaccinated persons, even though both had similarly high initial viral loads. Less viral load means less viral replication; thus, less frequent mutations and fewer chances of dangerous mutants.
A recent unpublished study confirms this notion. Researchers at the University of Maryland, U.S., used bioinformatics tools to analyze any changes in Delta variant’s genomic sequences following vaccination campaigns. Their results provide the first evidence that increasing vaccine coverage decreases the Delta variant’s mutation frequency in 16 countries.
“Our observations showed that countries with higher vaccination rates generated fewer mutations versus low vaccinated countries,” the study authors concluded. “This suggests that there is less of a chance for the virus to gain more virulent mutations in high vaccinated countries.”
* Source: Yeh and Contreras (2021). “Full vaccination is imperative to suppress SARS-CoV-2 delta variant mutation frequency.” MedRxiv. Australia (AUS), France (FRA), Germany (GER), Indonesia (IDA), India (IND), Ireland (IRL), Israel (ISR), Italy (ITA), Japan (JPN), Mexico (MEX), Netherland (NED), Norway (NOR), Portugal (POR), Singapore (SGP), Spain (ESP), Switzerland (SUI), Sweden (SWE), Turkey (TUR), United States (USA), and United Kingdom (UK). The graph shows that SARS-CoV-2 Delta’s genomes in countries with high vaccine coverage have fewer mutations.
Darwinian evolution, however, depends on two basic factors: random mutations and natural selection pressure. Genetic mutations arise at random, which may either improve, weaken, or do nothing to the organism’s fitness to survive in the environment. Nature, thus, imposes selection pressure that favors the proliferation of beneficial mutations.
The above study shows that vaccination decreases the frequency of random mutations, but it can’t say anything about selection pressure. As mentioned above, imperfect vaccines can create selection pressure, in which vaccine-resistant mutants have a higher chance of surviving and proliferating.
But there’s a catch: selection pressure works on a continuum rather than binomial ‘yes’ or ‘no’ conditions. The stronger the selection pressure, the harder the viruses — or any other biological entity— have to work. The harder they have to work, the more challenging it is to overcome the selection pressure, and the lower the chance of success is.
So, the more important question is not whether Covid-19 vaccines will impose a selection pressure, but how strong is the imposed pressure?
Fortunately, the current Covid-19 vaccines have worked better than expected, and the imposed selection pressure is powerful. Even though the Covid-19 vaccines were not designed to elicit sterilizing immunity, they still reduce infection and transmission rates. For example:
- A published study from Scotland found that Pfizer’s mRNA vaccine prevented 79% and AstraZeneca’s DNA vaccine prevented 60% of infections from the Delta variant. These numbers are 92% and 73%, respectively, for the Alpha variant.
- An unpublished study from the U.S. found that Moderna’s mRNA vaccine prevented 86% of infections when Delta is widespread. This number is 76% for Pfizer’s mRNA vaccine.
- An unpublished study from Israel found that Pfizer’s mRNA vaccine reduced the risks of infection amidst Delta’s spread by 39%.
- For non-Delta variants, the vaccines are even more effective at stopping infection and transmission.
Although the Covid-19 vaccines don’t fully stop infection, they at least reduce infection rates and, thus, transmission too. (Transmission isn’t possible without infection, but infection doesn't always lead to transmission.) But this notion may change in the future given the scarcity of studies that measured vaccine effectiveness against infection or transmission from Delta; nearly all of them have investigated symptomatic disease or hospitalization instead.
So, the vaccines are still suppressing the evolution of SARS-CoV-2, including Delta, but with less suppressing power than against non-Delta variants. But this also comes at the trade-off of selecting for the survival of vaccine-resistant mutants — if such mutants arise from random mutation and if such mutants are vaccine-resistant enough to survive the selection pressure from the vaccine. If SARS-CoV-2 managed to overcome such odds, we would need to update our vaccines, and the evolutionary battle resumes.
Are vaccines innocent?
Back to the introductory paragraph, did the Covid-19 vaccine clinical trials instigated the emergence of VOCs? No, because mutations that produce such VOCs arise at random due to imperfect genetic replication.
Did the vaccines promote the survival of VOCs? Yes, because vaccines impose a selection pressure that only allows the survival of vaccine-resistant mutants. But vaccine-imposed selection pressure is powerful, albeit imperfect.
Still, theories like these can’t tell us how much of a role had vaccines played in the emergence of VOCs.
On the one hand, it’s hard to imagine how a few thousand participants in the vaccine clinical trials are sufficient selection pressure to drive the spread of VOCs. On the other hand, it’s difficult to dismiss the fact that VOCs emerged soon after the initiation and within the proximity of vaccine clinical trials without suspecting anything.
Can we find out? I highly doubt it, though. Even if we trace the first SARS-CoV-2 sample that contains the specific VOC, how can we be sure if that sample is the index case? (Think of index case as patient zero.) Even if we sequenced the SARS-CoV-2 genomes from samples collected in the vaccine clinical trials and found a VOC, how can we be sure if the vaccine is responsible or it’s just a coincidence? We can’t.
With all that said, even though vaccines may not be truly innocent, depending on how you look at the situation, vaccines are not to blame.
Many past vaccines do not provide sterilizing immunity, yet they have greatly suppressed viral evolution for many years, as evidenced by the scarcity of vaccine-resistant pathogens emerging after vaccination programs (see figure below). After all, it’s much more challenging for pathogens to overcome the selection pressure from a good vaccine compared to antibiotics and antimalarials.
* Source: Kennedy and Read (2018). “Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance.” PNAS. The figure shows that vaccine resistance is far less likely to evolve than drug (antimalarial and antibiotic) resistance, as evidenced by the length of the red lines before the “x” mark.
Ultimately, vaccines are just one of our tools to fight pathogens, but pathogens can also fight back. Some anti-vaccine views have simply overestimated the effects of the latter and underestimated the former.
In other words, vaccines are our way of engaging in an evolutionary arms race with the pathogen. We may win, lose, or reach a stalemate. For example, we eradicated smallpox with vaccines, but we failed many times to develop an effective vaccine for the human immunodeficiency virus (HIV), and we have reached a stalemate with the seasonal influenza viruses.
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