Masks Mexico mural
Studies show hybrid immunity mounts a more vigorous action compared to natural immunity from previous infection, or a double dose of any vaccine. Image Credit: AFP


  • When previously infected individuals are vaccinated with just one dose, the effect is similar to two doses, but with a much stronger antibody response.
  • Studies show hybrid immunity mounts a more vigorous action compared to natural immunity from previous infection, or a double dose of any vaccine.
  • This combination of natural immunity with vaccine-generated immunity also results in a much broader cross-protection from SARS-CoV-2 variants, several studies show.
  • To date, hybrid immunity (immune response for prior COVID, plus one-dose vaccine) has not been beaten or matched by any 2-dose vaccine or mix/match combination.

Vaccination of previously-infected persons is now a reality. What's the effect, or benefit? It turns out when people who recovered from COVID-19 get a jab against SARS-CoV-2, people pile up a high wall against reinfection — better known as “hybrid immunity”.

Today, thanks to teams of researchers who have done independent clinical work, the underlying process behind this is now better understood. Scientists have bridged the knowledge gap on how much vaccinations among previously infected persons affect their response to a possible reinfection, with reports published in Cell and Clinical and Experimental Immunology.

Here’s what they found:

What's hybrid immunity?

It’s what happens when previously infected individuals are vaccinated with just one dose, specifically when using an mRNA vaccine. Researchers found that when natural immunity to SARS-CoV-2 is combined with vaccine-generated immunity, a larger-than-expected immune response arises.

One data set that investigated this phenomenon shows up to 100x antibody response in those with “hybrid immunity”.

How does it work?

Clinical researchers showed COVID-19 patients who had recovered and then got vaccinated had the highest antibody count in their blood samples. 

Hybrid immunity
Hybrid vigour immunity with COVID-19 vaccines: Hybrid vigour can occur when different plant lines are bred together and the hybrid is a much stronger plant. Something similar happens when natural immunity is combined with vaccine-generated immunity, resulting in 25 to 100 times higher antibody responses, driven by memory B cells and CD4+ T cells and broader cross-protection from variants. Image Credit: Science

A breakthrough study led by Prof. Alessandro Sette and Prof. Shane Crotty published in Cell describes how CD4+ T cells, CD8+ T cells and neutralising antibodies all contribute to control of SARS-CoV-2 in both non-hospitalised and hospitalised cases of COVID-19.

“Overall, the strength and breadth of the antibody responses after vaccination of previously SARS-CoV-2–infected persons was unanticipated,” wrote Crotty of the Center for Infectious Disease and Vaccine Research at the University of California, San Diego.

They found that antibodies do protect against SARS-CoV-2 reinfection, but only to a limited extent. There are other mechanism at work: more importantly, they found T cell responses against SARS-CoV-2 in natural infection are quite broad. As scientists investigate the relationships between immune responses and SARS-CoV-2 infection, one picture has emerged: CD4+ T cells, CD8+ T cells, and neutralising antibodies all contribute to control of viral infection.

Do vaccinations enhance immunity of previously-infected individual against reinfection?

Yes, according to the several peer-reviewed studies.

Research published in Clinical and Experimental Immunology in June 2021 further bolsters this conclusion. It examined data on real-time assessments of adaptive immune responses (which include CD4+ /CD8+ T cells, "natural killer" T cells, memory B cells and T follicular cells) specifically against COVID-19 peptides in infected and normal individuals.

Stan C. Jordan of the Cedars-Sinai Medical Center, Los Angeles, led a research team that published results of a study showing innate and adaptive immune responses to SARS-CoV-2 in humans, its relevance to acquired immunity and vaccine responses.

T cells
The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. Image Credit: Cell

Another study came out of a cohort of UK health care workers given the Pfizer/BioNTech vaccine in which half of the participants had experienced natural virus infections early in the pandemic.

In a pre-print published in bioRxiv on August 8, 2021, Paul Bieniasz, a virologist at the Rockefeller University, and his colleagues found antibodies in individuals that can strongly neutralise the six variants of concern tested, including Delta and Beta — as well as several other viruses related to SARS-CoV-2, including one in bats, two in pangolins and the one that caused the first coronavirus pandemic, SARS-CoV-1.

On August 30, 2021, Emily R. Egbert published in in the journal JAMA another example of hybrid immunity benefit with respect to durability of antibody levels to 10 months in health care workers.

Still another study posted August 31, 2021 on the medRxiv biology pre-print server confirmed hybrid immunity, i.e. single-dose COVID-19 vaccines in healthy individuals with past COVID-19 infections "seem to provide better immunity than double doses in COVID-19-unexposed individuals". The study, led by Padmanabha Shenoy of India's Center For Arthritis and Rheumatism Excellence, showed mean antibody titres (10076.8±8998) in the infection+single dose vaccine group were at least 6-100x higher than in the other groups: natural infection, single-dose vaccine, double dose vaccine groups. It is not known, however, whether the same is true for patients with autoimmune rheumatic diseases (AIRD) who are on immunosuppressants, the researchers cautioned.

What’s the driver behind hybrid vigour immunity?

Researchers have shown what happens to the immune system: when a natural COVID infection occurs, the body’s own innate and adaptive defences kick in.

DIVISION OF LABOUR: What is the function of antibodies and T-cells?
When an individual is infected with COVID, an immune response kicks in to control SARS-CoV-2 infection.

In simple terms, antibodies mostly stop viruses outside of cells; T-cells stop viruses inside of cells.

Prof. Alessandro Sette and Prof Shane Crotty explained in Cell (January 12, 2021) that this is the “division of labour” in the human body’s innate immunological mechanisms which has proven to be a successful complementary approach to control most viral infections.

So it’s widely known that, in case of a natural infection, the body’s “adaptive immune” immediately springs into action. But there’s a problem with this: adaptive immune response takes time to develop.

Why is it a problem?

The researchers seem to agree on one thing: early adaptive immune responses are beneficial; adaptive immune responses are just too late. As adaptive immune response takes time to develop, it leads to a fundamental and undesirable result — many cells are already infected by the time an antibody response develops.

In this case, the virus gets a huge advantage: unfettered replication in the upper respiratory tract (URT) and lungs. It only gets worse: it also fails to “prime” an adaptive immune response for a long time, resulting in conditions that lead to severe-enough lung disease, that leads to hospitalisation.

This also happens when a pathogen (virus, new variant) is particularly efficient in evading immune response, a person has defective innate immunity — or a delicate combination of both.

One study conducted by Moderbacher C Rydyznski (published September 16, 2020 in Cell), shows why the elderly have less ability to mount a T cell response quick enough to recognise the new virus. The reason: elderly individuals have a smaller T cell pool — which then hampers neutralising antibody responses, because neutralising antibody responses are generally T cell-dependent.

That’s why they are prioritised in vaccination schedules. So antibodies, by themselves, cannot clear an ongoing infection. They also need other components (helpers) of the immune-response mechanism to act up: Specifically, B cell and T cells. These are the body’s own fighters that are now seen behind the hybrid immunity boost.

What’s the evidence of this immune mechanism?

One evidence: single-dose vaccination adds immune protection for people with prior COVID, with 25-100 times higher antibody response, along with B cell and T cell response, as explained by the Crotty-led study.

antigens vs antibodies pathogens epitopes
The antibodies bind to a specific "epitope" on SARS-CoV-2 (cause of COVID-19) that is shared with SARS-CoV-1 (the virus that causes SARS), which may make it more difficult for the virus and its variants to develop resistance.
To better understand how the immune response mechanism works against COVID, clinicians count antibody “titres”.

An antibody titre is a type of blood test that determines the presence and level (titer) of antibodies in the blood.

Most clinical researchers have noted the absence of a correlation between neutralising antibodies and recovery from COVID-19. On the other hand, SARS-CoV-2-specific CD4+ T cells and CD8+ T cells strongly correlated with reduced disease severity. Researchers conclude that B cells and T cells are the key actors in fighting primary SARS-CoV-2 infection.

What are the components of the adaptive immune system?

What immunologists call the human “adaptive immune system” has three components — B cells (the source of neutralising antibodies), CD4+ T cells, and CD8+ T cells. Together, they hold the key to the control of most viral infections.

Immunity 3 types
IMMUNITY TYPES: (1) Innate immunity includes the external barriers of our body — the skin and mucous membranes of the throat and gut. This response is more general and non-specific. (2) If the pathogen manages to dodge the innate immune system, adaptive or acquired immunity kicks in. Adaptive immunity protects us from pathogens. It develops as we go through life. As we are exposed to diseases or get vaccinated, we build up a library of antibodies to different pathogens. This is sometimes referred to as "immunological memory" because our immune system "remembers" previous enemies. (3) Passive immunity is a type of immunity that is "borrowed" from another source. For instance, a baby receives antibodies from the mother through the placenta before birth — and in breast milk following birth. This passive immunity protects the baby from some infections during the early years of their life.

What’s the function of B cells, CD4+ T cells and CD8+ T cells?

For decades, immunologists have scrutinised the specific functions of B cells, T cells, CD4+ T cells, and CD8+ T cells. They have scrutinised their interplay with innate immunity. In recent months, they have sliced and diced clinical data to glean implications for COVID-19 vaccines and immune memory against re-infection. In a nutshell, they work as a team. But they have specific roles — in different viral infections and in vaccines.

B cells:

They fight antigens (like bacteria and viruses) by making Y-shaped proteins called antibodies. These antibodies are specific to each pathogen and are able to lock onto the surface of an invading cell and mark it for destruction by other immune cells.

T cells burn B cells
Image Credit: Jay Hilotin / Gulf News

CD4+ T cells:

T-cells are a subset of white blood cells that play an important role in the body's immune system. CD4 is a protein found on certain immune cells (T-cells, macrophages, monocytes) CD4 T-cells are considered "helper" cells because they do not neutralise infections; rather, they trigger the body's response to infections.

In the case of SARS-CoV-2 infections, CD4+ T cells are able to differentiate into a range of “helper” and “effector cell” types, with capacity to instruct B cells, help CD8+ T cells, recruit innate cells, have direct antiviral activities, and facilitate tissue repair.

CD8+ T cells:

They are classified as such because of the type of protein on their surface — play the part of "killer" cells by producing substances (antibodies) that help fight off viruses and other foreign invaders.

Based on numerous studies, clinicians have found among COVID patients the presence of both CD4+ T cells and CD8+ T cells. These two types of immune cells are directly correlated with reduced disease severity among COVID-19 patients.

Clinical evidence shows, thus: patients with moderate/less severe COVID cases were found with SARS-CoV-2-specific CD4+ T cells and CD8+ T cells. On the other hand, there were less neutralising antibodies found in the blood samples of the same individuals. Given the correlation, it’s been hypothesised: T cells are the front-liners in the body’s fight against SARS-CoV-2 infection.

Hybrid immunity: At least one study shows that when previously-infected individuals are vaccinated with just one dose, specifically when using an mRNA vaccine, they get a more vigorous response compared to natural immunity (from infection), or a double-dose vaccine (artificial infection).

Herd immunity: It can be reached when enough people in the population have recovered from a disease and have developed protective antibodies against a specific pathogen.

Do B cells find it hard to recognise the variants' mutated spike proteins in SARS-CoV-2 variants of concern?

Scientists have asked themselves whether the reductions in neutralising antibody response (mediated by vaccinations) are due to intrinsically low antigenicity of the variants (or VOCs). Specifically, they asked the question: is it intrinsically challenging for B cells to recognise the variants' mutated spike proteins?

The answer: “No”.

A team of researchers led by Thandeka Moyo-Gwete of the National Institute for Communicable Diseases, Johannesburg, South Africa studying the Beta variant of concern (codenamed B.1.351, first reported in South Africa), showed that neutralising antibody responses were robust against that variant and the ancestral strain.

Immune System
Image Credit: Gulf News

What’s the significance of the findings?

The researchers found that after vaccination of individuals previously infected with non-B.1.351 SARS-CoV-2, neutralising antibodies against B.1.351 were about 100 times higher than after infection alone and 25 times higher than after vaccination alone — even though neither the vaccine nor infection involved the B.1.351 spike.

The researchers found that after vaccination of individuals previously infected with non-B.1.351 SARS-CoV-2, neutralising antibodies against B.1.351 were about 100 times higher than after infection alone and 25 times higher than after vaccination alone — even though neither the vaccine nor infection involved the B.1.351 spike.


This is significant: it shows enhanced “neutralising breadth”, first reported by scientists like Stamatatos and then confirmed by other research groups. The other research team, based in the UK and led by Catherine Reynolds, of the Department of Infectious Diseases, Imperial College London, reported their findings in Science on June 25, 2021. It showed a significant antibody boost from a previous infection, followed by a vaccine — specifically, Pfizer’s mRNA shot.

Reynolds' team found that antibody and memory responses in individuals vaccinated after infection were substantially boosted "to the extent that a single vaccine dose is likely to protect against the more aggressive B.1.1.7” (Alpha variant, first reported in the UK). “It is possible”, researchers stated, “that the messenger RNA vaccine has an adjuvant effect, biasing responses toward antibody generation.”

If the adaptive immune response starts too late, fatal COVID-19 appears to be a situation where viral burden is high in the absence of a substantive adaptive immune response.

Scientists hypothesise that the innate immune system tries to fill the vacuum left by the absence of a T-cell response, by attempting to control the virus with an ever-expanding innate immune response.

The result: a massive innate response that leads to excessive lung “immunopathology" (immune responses associated with disease).

Many studies found that severe COVID-19 disease is usually associated innate cytokine/chemokine signatures of immunopathology, alongside high levels of neutrophils (the most common cell type of the innate immune system) in blood, and huge amounts of neutrophils in lungs.

Doctors call this "end-stage COVID".