Immunologically, Hybrid Immunity Makes Sense
It is becoming clear that hybrid immunity, the immunity provided by a combination of infection and vaccination, offers better protection with diverse antibodies against subsequent COVID-19 infection than vaccination or infection alone, wrote a recent editorial published by The Lancet Infectious Diseases.
However, the real-world immunity picture is very complex.
People differ not only in their history of infection timing and infecting variant but also in the type of vaccine they received, how many doses, and finally, how well their immune system responded, wrote this unsigned editorial published on November 10, 2022.
'The injection of antigens provokes a qualitatively different immune response than the infection of respiratory epithelial cells.'
Excerpts from this edited editorial are inserted below:
Immunologically, it makes sense that hybrid immunity provides better protection.
Irrespective of whether an antigen is introduced as a vaccine or due to pathogen replication, repeated exposure stimulates B cell responses and antibody production.
Most people with hybrid immunity will have encountered SARS-CoV-2 antigens more often than people who were only vaccinated or only infected.
Additionally, the quality of the immune responses differs.
Infection exposes the body to a range of antigens coming from different parts of the virus; mRNA and virus-vectored vaccines express only spike, which is the most important vaccine target on the virus surface and exposed to secreted antibodies.
However, other antigens are also important for T cell responses.
Furthermore, most COVID-19 vaccines administered so far target the ancestral spike from the SARS-CoV-2 beta coronavirus circulating during the early stages of the pandemic.
Currently, circulating variants have accumulated spike changes that enable them to evade most antibody recognition.
The positive aspect is an infection with one of these newer variants stimulates B cells with antigenically divergent spikes, broadening the immune response.
The balance between the recall of 'ancestral' immune responses and the development of 'novel' responses is not entirely clear.
There is some evidence of imprinting, that is, preferential recall of old immune responses.
Immune imprinting limits a person’s immune response against future variants.
However, the superiority of hybrid immunity tempers concerns somewhat, as the strength of hybrid immunity tends to depend on how closely the first infecting variant matches the subsequent one (although results are complex to interpret due to the waning of immune responses).
Innate immune responses and inflammatory stimuli 'orchestrate' the adaptive immune response.
The site of exposure also influences the quality of responses.
While SARS-CoV-2 infection of the upper respiratory tract induces mucosal IgA, current COVID-19 vaccines induce systemic IgG.
Systemic IgG is also produced after infection and is effective at targeting the coronavirus in the lung but generally much less so in the upper respiratory tract.
Immunologically it makes sense to favor hybrid immunity.
However, we would like to strongly caution against the conclusion that hybrid immunity should be a public health measure and that people should not protect themselves from infection or even be encouraged to acquire the infection to gain superior hybrid immunity.
Any infection comes with risks, both during the acute phase and long-term, such as an increased cardiovascular risk or Long Covid.
Unfortunately, the concept of hybrid immunity has become highly polarised.
So, where do we go from here?
Chequered immunity patterns in the population, waning immune responses, and the rise of immune-evasive variants such as BQ.1.1 or XBB, which might threaten protection afforded by hybrid immunity, require a multi-layered approach.
First, we need an agile, scalable, and fast infrastructure to develop and approve new vaccines that either target emerging variants, are pan-variant and/or provide mucosal protection.
Moreover, suppose there are political debates regarding hybrid immunity's benefits.
In that scenario, they should focus on people who have had no access to COVID-19 vaccines during the pandemic and who would clinically benefit from one today.
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