A personal view published by Milne and others in The Lancet Respiratory Medicine October 21st 2021, looks at this.  It is further discussed by Altmann and others in a comment published October 21st 2021. 

Many nations are pursuing the rollout of SARS-CoV-2 vaccines as an exit strategy from unprecedented COVID-19-related restrictions.  However, the success of this strategy relies critically on the duration of protective immunity resulting from both natural infection and vaccination.

SARS-CoV-2 infection elicits an adapted immune response against a large breadth of viral epitopes, although the duration of the response varies with age and disease severity. 

Current evidence from case studies and large observational studies suggests that, consistent with research on other common respiratory viruses, a protective immunological response lasts for approximately 5-12 months from primary infection, with re-infection being more likely given an insufficiently robust primary humoral response.  Markers of humoral and cell-mediated immune memory can persist over many months, and might help to mitigate against severe disease upon re-infection. 

Emerging data, including evidence of breakthrough infections, suggest that vaccine effectiveness might be reduced significantly against emerging variants of concern, and hence secondary vaccinations will need to be developed to maintain population level protective immunity.  

Nonetheless, other interventions will also be required with further outbreaks likely to occur due to antigenic drift, selective pressures for novel variants, and global population mobility.  

This duration of immune protection has crucial implications for the implementation of booster vaccine programmes – including the need for and timing of additional doses – which are sources of intense debate amongst both the scientists and policymakers.

Health policy makers have the unenviable task of developing strategies to reduce the burden of disease in the face of many points of uncertainty and controversy, including those related to the emergence SARS-CoV-2 variants of concern and the equitable distribution of vaccines. 

Booster programmes require adequate vaccine stocks, national supply and implementation logistics, and the rationale for age or risk group prioritisation, but also the challenge of yet more uncharted immunology for which the existing evidence bas is in.

In a world in which booster recipients will be drawn from those with variable prior immunity – which might be based on previous infection, often overlaid with vaccination with an mRNA or adenovirus vector-based spike vaccine – what form should a booster dose take, and when might it most advantageously be given?

Added to this is consideration of the substantial geopolitical and ethical implications of booster vaccination programmes, including the question as to whether it is appropriate to give what has been described as an extra life jacket to the privileged few when many of the world have yet to receive any life jacket at all.  

Intricacy of these deliberations is demonstrated by the divergent booster programme strategies of countries such as the UK, which has a cautious stratified booster roll-out, Israel hard-line revision of the green passport approach and USA ongoing reappraisals but moving towards a highly targeted booster programme.

The basic immunology evidence base that underpins the current deliberations has been evaluated by Milne and colleagues.  As with so much that we have had to confront in the pandemic, decisions on booster programmes represent real-life choices that sit at the interface between immunological, epidemiology data on SARS-CoV-2-related morbidity and mortality.  

Until recently, there was no clear consensus on the serum half-life of protective, neutralising antibodies after either natural infection or vaccination.  

Initial assumptions were that poor durability of protective antibodies following seasonal infection by the human common cold coronavirus might be replicated with SARS-CoV-2 – the fact that we succumb to winter colds caused by the same viruses year after year is a stark warning about the possibility of rapidly waning protection.  

The underlying mechanism of re-infection with common cold coronaviruses is generally thought to involve coronavirus adaptations that subvert innate pathways such as those leading to production of type I interferons. 

As longitudinal data has emerged from cohorts infected by SARS-CoV-2, interpretation of findings on waning immunity has become a source of ongoing debate.  

With estimates of a serum half-life for neutralising antibodies of more than 200 days, along with evidence of well sustained T-cell and B-cell memory and an improving B-cell repertoire due to affinity maturation, this concept that the immune response develops through a progressively more focused and tightly binding antibody repertoire, immune protection might be expected to last about one to two years after infection.

Since the end of 2020, data on immunity from countries with vaccination programmes have been overlaid with the effects of diverse spike vaccine platforms, each with distinct profiles of mean decline in neutralising antibodies and vaccine response kinetics.  

During this time, variants of concern have also emerged, notably the increasing dominance of the delta variant, which is associated with 5–10 times fall in neutralising antibodies.

Although basic immunology findings predict that the vast majority of people would nevertheless have sufficient protection to avert any risk of infection, real-world data have been more salutary.  

Data from individuals who received the Pfizer vaccine, especially those over the age of 60, who were vaccinated early in the programme, show susceptibility to breakthrough infection caused by the delta variant.  

Breakthrough infections are correlated with diminished antibody titres, especially at six months or more after the second vaccine dose.  A third booster dose is sufficient to flatten the curve of breakthrough cases, even in areas where the delta variant is dominant.  

On the one hand, this can be read as a good news story, calm, determined rationale immune monitoring managing to largely mitigate the next public health disaster.  

On the other hand, it is a sobering reminder of what a formidable pathogen we face, such that all traditional, textbook immunology assurances that T-cell and B-cell memory priming will provide lasting protection look a little thin.  

Finally, there is a need to confront the detail of protective immune repertoires and immune imprinting.  

It is already known that the immune response elicited by first-generation vaccines results in wide variability in neutralisation of current variants of concern, and that imprinting of the immune repertoire by previous exposure to the virus can differentially shape the protective response.  

Decoding these patterns and optimising protection against future variants will depend on fine mapping of cross-protective epitopes and making informed choices about which spike sequences to adopt for future booster dose programmes.  

The optimum COVID-19 vaccination strategy for the next few years is currently far from obvious, but probably not just a matter of using the sequence of the most recent variant of concern.

The London General Practice the leading London doctors’ clinic in Harley Street commends the Government on its vaccination programme but encourages those who are eligible for a booster to enrol and uptake.

Dr Paul Ettlinger

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