In this study, serum samples collected from people after one or two doses of the Pfizer BioNtech COVID-19 vaccine were tested for their ability to effectively neutralise the original (vaccine) strain of SARS-CoV-2 and four variants of concern, including the Delta (so-called India) variant. One strength of this study is that the serum samples were tested against each virus strain at the same time, allowing direct comparison of the data. It is clear that neutralising antibody concentrations against the Delta variant are lower than against the other strains, with the average concentration being at the lower end of the range seen for the vaccine strain. However, it is also the case that antibodies able to neutralise the Delta variant were identified in almost all samples, albeit at lower concentrations.

Comparing these antibody titres to previous data on vaccine efficacy suggests that the vaccine may offer somewhat less protection against infection with the Delta variant than against other variants and may thus have a lesser impact on transmission of this strain.

However, these data cannot tell us whether the vaccine will be any less effective at preventing severe disease, hospitalisation and death; we need to wait for the actual data on these outcomes.  There are reasons to be optimistic on this score, as other immune responses (such as T cells) also contribute to protection against severe disease and these may be less affected by the mutations that affect antibody neutralisation.

With cases of the Delta variant rising rapidly in the UK population, it is important to know how well the current COVID-19 vaccines will protect us against it. This latest study from the Francis Crick Institute and the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre Legacy study has looked at how well the antibodies in serum from people who have received the Pfizer/BioNTech vaccine can neutralise the different variants. There is less neutralising antibody against the new Delta variant in comparison with the previous Alpha variant. The antibody protection is on a par with levels of neutralising ability against the Beta variant. Antibody neutralising ability may not be the only determinant of immunity against SARS-CoV-2 but it has been shown to correlate quite well in other studies.  It will be important to look for real-world data as it emerges to determine the significance of this information, we have already seen some indication of low protection against the Delta variant with only one dose of vaccine in early PHE data.

This new information highlights the importance of monitoring emerging strains of the virus and how well the vaccines protect against them.  At this time, it shows that two doses of vaccine are critical for protection and therefore supports the JCVI updated guidance to decrease the time interval between vaccine doses to eight weeks for people over 50 or who are clinically vulnerable.

These are interesting and important results which add to our knowledge about vaccine-induced antibody-mediated immunity to different SARS CoV2 variants including the delta variant first reported in India and now being seen more widely in the UK.

The newly developed laboratory system used to measure virus neutralising activity by the group reporting the results has not been used previously in vaccine efficacy studies, so we do not know very much about how well it predicts protection against infection or mild or severe disease.  In addition, we do not yet have a clear level of antibodies that accurately predicts protection even with the tests which we are more familiar with. Consequently, the exact importance of these results is uncertain. We also know that the Pfizer vaccine can be highly protective even in the absence of neutralising antibody and only after one dose.

The results correlate well with real life effectiveness data published by Public Health England last week suggesting that there is some reduction in protection against symptomatic disease caused by this new variant.

Overall these results reinforce the importance of close surveillance of trends in this new variant and vaccine effectiveness over coming days and weeks.

This is a rather elegant study showing us that much of what has been concluded for the other variants is even more the case for the delta variant. That is, two doses of vaccine gives most people such a high level of neutralising antibody that even with some loss of this protective headroom by variants, protection will be largely in place. However, when one sees that the reduced protection is even more pronounced for the delta variant than for the other variants of concern, and that people with either zero on only one vaccine dose may be really quite vulnerable, data such as this may be taken as a caution to ramp up progress to full, widespread delivery of two vaccine doses.

The purpose of vaccination is disease prevention, rather than the generation of neutralising antibodies; but the quantity and quality of antibodies generated may be part of the mechanism by which vaccines prevent disease.

We should also bear in mind that the severity of disease prevented is highly significant. Vaccines – including COVID-19 vaccines – are generally most effective at preventing severe disease and death, and progressively less effective against less severe disease and asymptomatic infection.

It takes a long time to learn about vaccine efficacy in clinical trials, or vaccine effectiveness in real world post-implementation studies: you have to accumulate cases of disease in people who have, and who have not been vaccinated.  So it is very useful to have “correlates of protection” which can allow vaccines to be evaluated in much smaller, easier-to-perform studies, measuring things like the quality and quantity of antibodies in vaccine recipients.

The study described in this letter to The Lancet is such a study, looking at likely correlates of protection against a number of variants or strains of the SARS-CoV-2 virus. Specifically, it looked at whether “neutralising antibodies” (Nabs) could be detected, and at the quantity (as measured by their “titres”) of such antibodies (NAbTs) following doses of the Pfizer BioNTech mRNA vaccine (BNT162b2).

The virus variants (which they refer to as “strains”) that they studied were:

• The original virus (which they refer to as “wild type” – although of course, all the variants studies arose “in the wild”).

• A strain with a mutation – an amino acid substitution at the 614th position -that was first isolated in the first wave of infections in the UK.

• The B.1.1.7 variant that the WHO now refers to as Alpha, which was first identified in Kent, UK1.

• The B.1.617.2 (Delta) variant, which was first identified in India.

• The B.1.351 (Beta) variant, which was first detected in South Africa in late 2020.

They found that the lower levels of neutralising antibody (NAbTs) were generated by the vaccine against the Beta and Delta viruses; and that this effect increased with age, with older people producing fewest such antibodies.  Consistent with recent reports that vaccine effectiveness following a single dose is lower for the Delta variant2 they found that the reduction in NAbTs was particularly pronounced in people who had so far only received a single dose of vaccine.

They also found that antibody levels against all variants declined in participants who were tested again 8-16 weeks after their second dose of vaccine.

These findings are interesting; but we should not read too much into them.

The PHE real world study did not report on more severe forms of disease, just symptomatic infection2.  Since Covid-19 vaccines are generally more effective at preventing more serious forms of disease, it is not unlikely that the reduction in effectiveness against hospital admission, critical care admission and death is considerably less than the reduction in effectiveness against all symptomatic infections.  (Only a small proportion of people with symptomatic infection go on to develop more serious forms of the disease).

And NAbTs are not all there is to know about immunity: other factors such as the presence of long-lived memory cells which can rapidly produce large quantities of antibodies on subsequent exposure, and other aspects of humoral or cellular immunity, such as killer T-cells are all likely to be important with Covid-19.  We are still learning – and this paper will be part of the learning – about the relative importance of the different aspects of the immune system.  Low NAbTs will not necessarily mean susceptibility to infection.  This paper is an important and useful part of the process of developing useful, laboratory-based, correlates of protection for Covid-19 and for variants of SARS-CoV-2.

We must expect to see more new variants arise: the more infections there are in the world, the greater the chances that new, more transmissible variants will arise.  It takes time to assess how transmissible each new variant is, whether it is clinically different (might it, for example, cause more severe disease, or cause symptoms in a higher proportion of school children), and whether they are likely to evade vaccines3.  Laboratory-based measures, which can be available rapidly, will help us to assess future new variants more quickly.

The authors discuss the longer prime-boost interval adopted, with great success so far at least, in the UK4.  Increasing the prime-boost interval generally enhances the quality and breadth of the immune response, leading to longer-lasting immunity.  (The same effect can be achieved by additional booster doses.)  Given the lower NAbTs against the Delta and Beta variants that they found after a single dose of vaccine (and the findings of the real-world study), the authors suggest that it might be worth reducing the prime-boost interval; giving the second dose sooner, at least for people in the higher risk categories, to maximise protection against these variants.

From the beginning of the vaccination programme, the bottleneck has been the availability of vaccines.  If you give one person a second dose sooner, another person will have to wait longer for their first dose.  Given that a single dose of vaccines is effective at preventing even disease caused by the Delta and Beta SARS-CoV-2 variants, this would shift risk from one person or group to another.  However, the authors only suggest doing this for people in the risk groups identified by JCVI for the first phase of the vaccination programme, while continuing to vaccinate other groups as we are doing at present, not reducing the vaccination interval for the lower-risk groups5.  This seems a sensible compromise.”

1. World Health Organisation. Tracking SARS-CoV-2 variants. 2021; Updated 31 May 2021; Accessed: 2021 (31 May): (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/).

2. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, et al. Effectiveness of COVID-19 vaccines against the B.1.617.2 variant [public pre-print]: Public Health England, 2021 (22 May);  (https://khub.net/documents/135939561/430986542/Effectiveness+of+COVID-19+vaccines+against+the+B.1.617.2+variant.pdf/204c11a4-e02e-11f2-db19-b3664107ac42).

3. English PMB. New variants will become routine. Peter English's random musings (blog) 2021; Updated 31 May 2021; Accessed: 2021 (31 May): (https://peterenglish.blogspot.com/2021/02/selected-questions-and-answers-about_1.html).

4. English PMB. The UK approach to COVID-19 vaccination: why was it so different? Drugs in Context 2021;10:2021-4-5. (https://www.drugsincontext.com/the-uk-approach-to-covid-19-vaccination:-why-was-it-so-different/).

5. Joint Committee on Vaccination and Immunisation (JCVI). Priority groups for coronavirus (COVID-19) vaccination: advice from the JCVI, 2 December 2020. Priority groups for coronavirus (COVID-19) vaccination: advice from the JCVI, 2 December 2020 2020; Updated 02 Dec 2020; Accessed: 2020 (03 Dec): (https://www.gov.uk/government/publications/priority-groups-for-coronavirus-covid-19-vaccination-advice-from-the-jcvi-2-december-2020/annex-a-covid-19-vaccine-and-health-inequalities-considerations-for-prioritisation-and-implementation).

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