How Hybrid Immunity Could Outrun SARS-CoV-2’s Evolution


We can achieve that with natural infection plus vaccination or with mixed vaccinations — so maybe we should rethink how vaccine boosters are given.

Amidst the push for global vaccination to end the Covid-19 pandemic, we have recently discovered the potential of hybrid immunity, the synergistic combination of different forms of immunity. There has probably never been a time where we study immunity so fiercely as the last 12 months. Believe it or not, there are only six hits on hybrid immunity (which are not even related to vaccines) in PubMed, a biomedical literature database, as of today. So, let’s see what hybrid immunity has to offer.

Natural vs. vaccine-induced immunity (in the context of SARS-CoV-2)

Immunity means resistance to a pathogen or infectious disease. This resistance comes from memory the immune system forms after seeing an infection or pseudo-infection (from a vaccine). Such memory helps the immune system to respond more effectively — in terms of B-cell and T-cell responses — when the host sees the same or a very similar pathogen again.

B-cells and T-cells make the adaptive immune system that adapts as the host faces new pathogens throughout life.

  • B-cells make antibodies that neutralize pathogens. Antibodies bind to a specific part of the pathogen to neutralize it, so that that part can’t bind to anything else. Antibody-bounded spike protein of SARS-CoV-2, for instance, would prevent the spike protein from binding to our cells.
  • T-cells are split into killer and helper T-cells. Killer T-cells kill abnormal cells, such as virus-infected and cancerous cells. Helper T-cells assist the overall immune responses, including killer T-cells’ and B-cells’.

Both natural infection and vaccination can induce immunity. But the two differ in antibody effectiveness — namely, specificity and durability.

Regarding antibody specificity, vaccines are usually designed to trigger antibody responses to the pathogen’s most crucial part. Nearly all the Covid-19 vaccines, for example, induce immunity towards the spike protein. SARS-CoV-2 uses its spike protein to infect cells, so neutralizing its spike protein is the surefire way to prevent cell infection.

In contrast, natural immunity isn’t very specific, where the immune system generates memory against various parts of the pathogen. Thus, some Covid-19 survivors have antibody memory against the membrane protein and nucleocapsid of SARS-CoV-2, which don’t seem to protect against Covid-19. And as a drawback, Covid-19 survivors may have weaker antibody immunity against the spike protein than vaccinated people (with mRNA vaccines).

Regarding antibody durability, vaccine-induced immunity (from mRNA vaccines) is longer lasting than natural immunity. This is expected given that vaccination helps the immune system make more spike protein-specific antibodies than natural immunity to begin with.

As you may have noticed, the above comparison was based on mRNA vaccines. mRNA vaccines are remarkably effective, as per how a vaccine should work.

But antibody effectiveness from other types of vaccines may not necessarily be better than natural infection (also called convalescent). Based on a research review, these less effective vaccines are CoronaVac (Sinovac, inactivated), Ad26.COV2.S (Johnson & Johnson, DNA), ChAdOx1 (AstraZeneca/Oxford, DNA), and Covaxin (Bharat Biotech, inactivated), as shown in this graph:
Antibody neutralization capacity and protective efficacy of vaccines vs. convalescent (naturally infected Covid-19 survivors).Khoury et al. (2021). Nature Medicine.

The other vaccines in the graph that induce greater antibody responses than natural immunity are rAd26-S + rAd5-S (Sputnik V, DNA), BNT162b2 (BioNTech-Pfizer, mRNA), NVX-CoV2373 (Novavax, nanoparticle), and mRNA-1273 (Moderna, mRNA).

Notably, in this graph, the 95% confidence interval (represented by the cross) is rather wide — indicating that some degree of overlapping may be present. (The 95% confidence interval is the range of outcomes that would apply 95% of the time.) This means that there’s hardly an absolute rule that one type of immunity is better than the other every time or in every case.

But note that natural immunity demands one to survive the infection first, as well as post-infection health consequences. It’s the survival of the fittest that can be ugly at times. Just remember the deaths Covid-19 has amassed.

Moreover, the effectiveness of natural immunity usually depends on the infectious disease’s severity. For SARS-CoV-2, although asymptomatic (no symptoms) and mild infections can still generate antibodies, such antibodies tend to wane quicker than those who had more severe infections.

Waning antibodies don’t necessarily mean lower protection in real life, however. Covid-19 survivors, including asymptomatic cases, also have T-cell memory that can kickstart antibody production in times of need. (Most studies on vaccine responses don’t measure T-cell responses because they are very tedious to do— not scalable.) But it’s also true that, among people with prior SARS-CoV-2 infection, those unvaccinated are more likely to get re-infected than those vaccinated, possibly due to waning antibodies.

Ultimately, natural immunity varies from person to person, making its effectiveness more difficult to predict. Vaccine-induced immunity, in contrast, comes from standardized dose and clinical data, so it’s easier to predict.

Natural vs. vaccine-induced immunity against SARS-CoV-2 variants of concern (VOCs)

The VOCs are SARS-CoV-2 mutants that are more transmissible, virulent, or resistant to medicines, diagnostics, or vaccinations than the original variant called wild-type. The present VOCs are Alpha (first discovered in the U.K.), Beta (South Africa), Gamma (Brazil), and Delta (India).

In the above section, we see that vaccine-induced immunity against the spike protein of wild-type SARS-CoV-2 is often better than natural immunity.

But if the spike protein is no longer as relevant— such as in the context of the mutated spike protein of VOCs — natural immunity might be better than vaccination. It’s might because some studies show so and some do not:
Shin Jie Yong

One major flaw in these studies (in Table 1) is that laboratory results may not always reflect what would happen in the real world.

To this end, one population-based, observational study from Israel (released last week, unpublished) found that risks of infection and symptomatic disease from Delta were 6-fold and 7.1-fold higher in the Pfizer (two-dose) compared to natural infection group. (This number was 13-fold in the unvaccinated group without natural immunity.) So, Pfizer’s mRNA vaccine took a blow here, providing less real-world protection against Delta than natural infection.

But note that this is just one study (there seem to be no other studies on this topic at present), so things might change as more research gets done.

Hybrid immunity: the strongest form of selection pressure

Thanks to the recommendation that Covid-19 survivors should still get vaccinated, we managed to discover that hybrid immunity against SARS-CoV-2 is possible. This is also called hybrid vigor immunity, a product of synergistic immunity strength from natural infection plus vaccination:
Hybrid immunity provides the strongest immunity (represented by tree's height) against SARS-CoV-2 than natural or vaccine immunity alone.Crotty (2021). Science.

A few published studies have found that antibodies from persons with both natural and vaccine-induced immunity were much more effective at neutralizing SARS-CoV-2 — both the wild-type and VOCs — compared to either one type of immunity by itself. These studies are detailed in Table 2 below.

Remarkably, in one of these studies, hybrid immunity also provided a 7-fold increased antibody neutralizing capacity against SARS-CoV-1 compared to mRNA vaccine immunity only. This number is 1000-fold if compared to natural immunity only. SARS-CoV-1, which caused the 2002/2003 SARS outbreak, is very different from SARS-CoV-2 — a 20% genetic difference. In contrast, the genetic differences between the wild-type and variants of concern of SARS-CoV-2 are only 0.5–0.7% at most.

This finding suggests that hybrid immunity is strong enough to protect against related pathogens that are also quite different from one another — that is, evolutionarily distant or divergent — for example, SARS-CoV-1 vs. Cov-2.
Shin Jie Yong

Unfortunately, none of those hybrid immunity studies (in Table 2) were about Delta. Nonetheless, the strength of Delta’s vaccine resistance lies somewhere in between Alpha and Beta (see Table 1 in the earlier section). So, if Beta can’t overcome hybrid immunity, the chances are that Delta can’t either.

Still, we shouldn’t underestimate Delta. Even though Delta is not as vaccine-resistant as Beta, Delta is the most transmissible variant by far — causing numerous vaccine breakthrough infections. Higher transmissibility gives Delta ample opportunities to mutate and evolve. There’s no guarantee that a hybrid immunity-resistant SARS-CoV-2 variant won’t emerge later.

But the possibility of this scenario happening is very slim. The stronger the selection pressure, the harder it is for the pathogen to overcome it. In this case, the selection pressure is hybrid immunity and the pathogen in SARS-CoV-2. This means that with hybrid immunity, winning the evolutionary arms race against SARS-CoV-2 may be within reach. But nothing in evolution is 100% certain, which is why may is the rational way to put it.

If hybrid immunity is achievable via mixed vaccinations, maybe we should rethink boosters

Memory B-cells actually have two functions. One is to make identical antibodies that neutralize the same target. The other function not many know is somatic hypermutation, where memory B-cells also create a collection of mutated antibodies that can neutralize mutants (mutated) of the target.

Mutated antibodies explain why antibodies from both individuals with natural or vaccine-induced immunity are still capable of neutralizing the mutated spike protein of SARS-CoV-2 VOCs to some extent.

Memory T-cells further aid the activation and proliferation of such mutated antibodies in times of need. And hybrid immunity also involves enhanced T-cell memory. A few studies have shown that previously infected individuals with SARS-CoV-2 get a boost in T-cell responses after vaccination.

Therefore, the key to hybrid immunity is having diverse forms of B-cell and T-cell memory that can react to diverse forms or mutants of a specific pathogen. And we get this through attaining various forms of immunity — which may not have to be natural plus vaccine-induced immunity.

A few studies in Germany have found that heterologous (mixed) vaccine doses— AstraZeneca’s DNA plus Pfizer’s mRNA vaccines — are safe and produced greater T-cell and antibody responses against SARS-CoV-2 VOCs compared to homogenous (same) vaccine doses:
Shin Jie Yong

Evidently, the research on mixed Covid-19 vaccinations still has a long way to go. We only have laboratory data on combined AstraZeneca’s DNA and Pfizer’s mRNA vaccines for now, which are promising so far. Still, at least in theory, other mixed vaccination plans should also confer hybrid immunity. Inactivated whole-virion vaccines may shine in this regard, since they closely resemble natural infection more than other spike protein-specific vaccines.

That said, if we can attain hybrid immunity via mixed vaccinations, perhaps a vaccine booster should be a different one than what was given initially. For instance, in Israel, people who received two doses of Pfizer’s mRNA vaccine are getting the third Pfizer’s dose. But maybe getting a non-mRNA vaccine as the third dose — such as Novavax nanoparticle, Sinovac inactivated, or Johnson & Johnson DNA vaccine— is the better booster.

Sure, a natural infection could also serve as a booster on top of vaccines. But we don’t have enough data to say if this is the better method to induce hybrid immunity. After all, the current studies on SARS-CoV-2 hybrid immunity (in Tables 2 and 3) studied infected people who were later vaccinated — not vaccinated people who later got infected — and people who received mixed vaccinations. Moreover, cases of vaccine breakthrough infections can still result in the debilitating long-Covid syndrome, so there’s a risk there.

Ultimately, hybrid immunity is definitely a topic worthy of further attention and research. Public health policies should really consider ways to implement hybrid immunity as a means to wrestle with the pandemic. Like it or not, we are already engaged in the evolutionary arms race against SARS-CoV-2, and we should aim to win. What that win looks like is debatable, though, another topic for another time.

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer


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