A scanning electron microscope image of SARS-CoV-2 (yellow) emerging from the surface of cells cultured in the lab. Image: NIAID/Flickr, CC BY 2.0
- A study published last month has motivated a sort of a paradigm shift in our understanding of the immunological responses to vaccines and infections.
- The study described original antigenic sin, wherein high-affinity memory B-cells inhibit the recruitment of naïve B-cells against a new pathogen.
- So if you had COVID-19 due to an infection by the ‘original’ strain, your immune system wouldn’t learn anything new from an infection of the omicron variant.
- The study confirmed exactly this, putting a big question mark over the utility of booster doses for vaccines developed based on the ‘original’ strain.
- Prime Minister Narendra Modi’s announcement to launch a free booster-dose campaign must be seen against this background.
Earlier this month, the Government of India declared free ‘precaution’ doses of COVID-19 vaccines for all citizens above 18 years of age at government vaccination centres from July 15 for 75 days. The announcement was to mark 75 years of India’s independence.
Most health experts have hailed this decision, yet it still merits a closer reappraisal – especially in light of recent knowledge. The questions, in effect, are whether we need to boost our existing population immunity and if ‘precautionary’ doses could help fight emerging sub-variants of the omicron variant.
The COVID-19 vaccines currently in use were designed to target the virus in its ‘original’ form more than two years ago. They confer a high level of protection against severe hospitalisation and death but little protection against mild symptomatic disease and infection, especially against the highly immune-evading omicron family of variants.
So as such, they have been a great tool with which to provide individual protection, especially against severe disease and death. This is no mean feat – but in the overall scheme of the pandemic, they fail to offer any resistance to additional waves of infections.
As a result, instead of a wall of immunity arising from vaccination, we have experienced wave after wave of new cases and a rapidly growing burden of long-term disease. We must remember that vaccines are a great public health tool. Their main goal, when used with this objective, is to protect communities from the ill-effects of a surging pathogen. The least ambitious goal of vaccination is to prevent us from dying.
The WHO and other international health agencies have spent many resources to prepare specific products as an exercise for pandemic preparedness in the past. Developing vaccines that are tailor-made to take on a pandemic pathogen should have been at the centre of any ‘pandemic control’ strategy. The attributes of a vaccine needed for a novel pandemic pathogen are different from a vaccine for an endemic illness.
Unfortunately, they have likely overlooked this critical aspect of vaccine development for the SARS-CoV-2 pandemic.
Why do we need boosters?
We know that even two doses of the current COVID-19 vaccines can confer a ‘good’ level of protection against severe disease, hospitalisation and death – even against the highly mutated omicron variant – through memory B and T cells’ responses.
But even with boosters, it is highly unlikely that protection against infection and mild to moderate disease will improve significantly, particularly against the current sub-variants of omicron, which are far more transmissible than their parent lineage ever was.
Their immune evasion is also extraordinary. For example, a triply vaccinated individual was found to have had only 5% of the neutralisation titres against the omicron variant that they did against the ancestral strain.
Further, whatever little augmentation in antibodies titres we have found following booster doses, the titres wane dramatically after a few weeks. A recent study reported that the protection gained from even a fourth vaccine dose will likely wane even faster than that conferred by previous boosters.
So unless booster doses strengthen our existing protection against severe disease to a considerable extent, there is no point boosting the entire population.
Boosters can be justified if they significantly ‘boost’ the existing protection provided by the two primary doses against severe disease and death, by strengthening our T-cell compartment.
An observational study from Israel examined the effectiveness of boosters at preventing severe outcomes. The authors of the study’s paper wrote that among “those aged 16-39 years, the rate of severe outcomes was too small for meaningful estimation of the booster effectiveness.”
In other words, severe disease was rare among those who were double-vaccinated and younger than 40 years – whether or not they had received a booster. So it’s almost futile to offer booster doses to people of this age group, or healthy individuals without any comorbidities or underlying conditions.
Immune imprinting and its implications
A study by Daniel Altmann, at Imperial College London, and his peers published last month in Science motivated a sort of a paradigm shift in our understanding of the immunological responses to vaccines and infections. Altmann et al. described a phenomenon called immune imprinting – known more traditionally as original antigenic sin (OAS) – and it has shaken the research community.
There had been some speculation of OAS from the beginning, when COVID-19 vaccine development had just started becoming familiar with the mutational abilities of the novel coronavirus. Researchers had suspected its existence in their studies – now, the study by Altmann et al. has confirmed it.
OAS describes a situation in which the first encounter with a pathogen, like a virus, dictates subsequent immunological responses thereafter. The original primed B-cell memory perpetually dominates the immune response at the expense of the development of new memory B-cells and neutralising antibodies against new viral epitopes1 or variants.
OAS operates through germinal centre reactions inside the lymph node, where high-affinity memory B-cells are produced. These cells are supercharged, in a manner of speaking, and inhibit the recruitment of naïve B-cells – B-cells that haven’t been exposed to antigens – against a new offending agent. The effect is a weak antibody response.
More simply, If you had COVID-19 due to an infection by the ‘original’ strain, your immune system wouldn’t learn anything new from an infection of the omicron variant. That is, your body will not learn to make antibodies or T-cells against new variants, and will instead continue to depend on the old response.
This is exactly what the Altmann et al. study confirmed.
The team analysed blood samples from healthcare workers in the UK who had received three doses of mRNA vaccines and had a past infection with different SARS-CoV-2 variants. They studied the level of neutralising antibodies and T- and B-cell responses against the omicron variant in these different groups.
They found that T- and B-cell responses among triple -vaccinated individuals were enhanced against all previous variants of concern but were blunted against the omicron variant.
The most dramatic finding was that, among triply vaccinated healthcare workers who had been infected during the first wave (i.e. by the ‘original’ strain), both neutralising antibodies and T-cell responses were thoroughly blunted against an infection of the omicron variant.
In other words, the study showed that an individual’s vaccination and infection history could and did influence their future immune response to variants, including the omicron variant.
One explanation for this is the observation that an infection by the omicron BA.1 strain after vaccination seems to trigger infection-blocking neutralising antibodies that recognise the ancestral strain of the virus – the one that vaccines are based on – better than they recognise the omicron family of variants.
OAS could be at work when different variants of the SARS-CoV-2 virus are in play. In retrospect, most of our vaccines that are based on the ancestral strain worked reasonably well against the alpha and the delta variants of concern – variants that hadn’t drifted significantly from their ancestor.
The omicron variant, however, arrived on the scene with 50-odd mutations in the spike protein region of the genome. As a result, the antibodies of vaccinated hosts failed to efficiently neutralise the new epitopes, and the full-blown impact of OAS came to the fore.
Could frequent boosting be counterproductive?
Thanks to OAS, if you have been exposed to the ‘original’ strain, you are unlikely to mount efficient neutralising antibody or T-cell responses against newer, more-different variants – no matter how many times you get exposed to these variants, and no matter how many times you inject yourself with a new shot of a COVID-19 vaccine. The vaccines based on the ancestral strain may compromise your immune system’s ability to react to newer variants.
So quite possibly, the unvaccinated may have a better immune response to a ‘scary’ new variant than the vaccinated and boosted. Those imprinted with the ancestral strain – through natural or vaccine-induced immunity – may be slower to respond to the new variant than those who haven’t been infected or vaccinated.
Further boosting with the current crop of vaccines, developed based on a significantly different strain (relative to the number of mutations), may not broaden your immune response but could in fact hinder it by further ‘back-boosting’ your memory B-cells’ population.
A short report published recently in the New England Journal of Medicine found that boosted individuals clear the virus more slowly than non-boosted individuals. So it’s possible that repeated boosting may make it harder to respond to future variants due to the inertia imposed by OAS.
Philip Krause, Marion Gruber and Paul Offit wrote in The Washington Post late last year about the futility, and even dangers, of repeated boosting (emphasis added):
“It’s also possible that repeatedly ‘training’ the immune system to fight the original virus could reduce the effectiveness of a variant-specific booster. … In other words, for those not in immediate need of a boost, there may be an advantage to waiting until a booster more closely aligned with circulating variants becomes available; boosting on the original antigen could be counterproductive.”
OAS beyond vaccination
The best way to analyse OAS is to look at someone who has never been exposed to SARS-CoV-2 (including through vaccination) and infect them with the omicron variant. Then, compare their immune response to someone who has been vaccinated but contracted a breakthrough infection.
Thus far, this type of study has not been conducted.
In fact, the biggest limitation of Altmann’s study is that it wasn’t equipped to answer the following question: “Does OAS occur only among vaccinated individuals or could it occur among naturally infected individuals as well?”
This is a critical question. We can only prove or disprove it if we have three cohorts: a naïve group without any exposure to SARS-CoV-2 infection or vaccines; a vaccinated group; and the group of people naturally exposed to the virus. A follow-up study of immune responses and appearance of disease in these cohorts following a breakthrough omicron infection could tell us whether OAS only affects vaccinated individuals or if it affects those who have naturally had COVID-19 as well.
For now, given the number of people who have been infected and/or vaccinated, such a study has been rendered hypothetical.
We have still not been able to figure out the exact correlate of protection against COVID-19 – that is, the substance that will at a certain concentration keep COVID-19 at bay. Most vaccine developers believe that neutralising antibodies are the cornerstone of protective immunity. They are right to a certain extent – but natural immunity following an infection is broader and has more forms than vaccine-induced immunity.
For example, we know that following a natural infection, both neutralising antibodies and mucosal immunity (comprising secretory immunoglobulin-A and memory T- and B-cells in tissues) provides an extra layer of protection that current vaccines fail to provide.
Then there are non-neutralising antibodies that may protect against infection. The paper of a study published in January this year reported that non-neutralising antibodies could protect against a SARS-CoV-2 infection by mediating phagocytosis. This would mean we have broader protection from antibodies than previously thought, making us less vulnerable to mutations of the virus.
Remember here that OAS operates only through the formation of memory B-cells that elicit neutralising antibodies against the imprinted antigens.
Utility of current vaccines
If future research confirms that OAS mainly occurs only with vaccines, the entire COVID-19 immunisation program will receive a big jolt.
A recent study from Qatar concluded that the protection that natural immunity confers against severe illness remains superior to that bestowed by COVID-19 vaccines. People who survived a COVID-19 infection and weren’t vaccinated had a very high level of protection against severe or fatal COVID-19.
“The effectiveness of primary infection against severe, critical or fatal COVID-19 reinfection was 97.3%, irrespective of the variant of primary infection or reinfection” and with no evidence of waning, according to Laith Jamal Abu-Raddad, the study’s lead author and a professor of population health science, Laith Abu-Raddad of Weill Cornell Medical College, New York.
That is, a person who has been naturally infected at any time during the pandemic is almost completely protected from severe disease and death against any future reinfection by any variant (including omicron). This is the same promise that the current COVID-19 vaccines make. They don’t prevent reinfection, only severe disease.
Another study published only last week, in The Lancet, hinted at the futility of repeatedly vaccinating convalescent individuals who already have a (relatively) high volume of neutralising antibodies. In their paper, the authors wondered “whether less frequent vaccination could maintain neutralisation breadth in those individuals”.
It seems quite unlikely that agencies like the WHO and the US CDC remain unaware of OAS. But they’re yet to acknowledge its existence, at least in public. The silence of vaccine manufacturers, on the other hand, is more understandable because they have invested heavily in vaccine development and production.
In India, Prime Minister Narendra Modi’s announcement to launch a free booster-dose campaign must be seen against this background. Only a few months ago, Serum Institute of India announced a halt to the production of its COVID-19 vaccines amid fading demand. The global adjustment to living with the virus has also diluted the need for booster doses.
Documenting OAS has many implications for the policy to continue with the current vaccines, which are based on the ancestral strain. Adding further boosters of the same strain wouldn’t only be superfluous but may prove counterproductive. Instead, studies have shown that natural infection provides an equivalent or slightly superior and longer lasting protection against severe disease than vaccination.
Where does this leave our existing COVID-19 vaccines? I think their only merit now is to protect those high-risk individuals who have comorbidities and have yet to contract a natural infection. A new infection, even with the omicron variant, may have serious and unpredictable consequences for these people.
The way forward
First, we need to develop new vaccines that target some of the conserved epitopes and provide mucosal immunity (immunity that acts at mucosal sites). Developing a variant-specific vaccine may also fail among those imprinted with the ancestral variant, either through vaccination or infection.
In fact, developing either a pan-sarbecovirus vaccine or a multi-variant vaccine could offer hope to prevent future waves.
Next, nasal vaccines are an exciting and feasible option. Some seven to ten companies are developing them. In a recent editorial for Science Immunology, noted immunologist Akiko Iwasaki and cardiologist Eric Topol strongly rooted for an ‘Operation Nasal Vaccine’ – a new mission to help us to quickly achieve population-wide respiratory mucosal immunity, thus putting us in far better position to contain the virus.
Through such an initiative, we could also get ahead of the virus and build on the initial success of our COVID-19 vaccines.
Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.
The part of the pathogen that draws the immune system’s attention.↩