key: cord-0020689-r4a5ae3s
authors: Bar-Zeev, Naor; Shet, Anita
title: Population science with individual-level data make for better policies
date: 2021-07-02
journal: Lancet Respir Med
DOI: 10.1016/s2213-2600(21)00236-8
sha: 64134533c006c832604673bb17d491971bc05096
doc_id: 20689
cord_uid: r4a5ae3s

nan

Leveraging its strong primary health-care system and universal health coverage backed by electronic data systems, well developed surveillance infrastructure, and high community demand, Israel has led a successful national rollout of Pfizer-BioNTech's BNT162b2 mRNA COVID-19 vaccine, achieving high population coverage at a rapid pace. 1 The lessons learned from assessing the rollout have broad relevance. In the Lancet Respiratory Medicine, Yaniv Lustig and colleagues 2 report the findings from their prospective, singlecentre cohort study of 2607 nSARS-CoV-2 seronegative health-care workers in Israel (72·2% female, mean age 47·7 years [SD 12·5]) evaluated for their immune responses over 5 weeks following the first vaccine dose, including a timepoint 1-2 weeks after the second vaccine dose at week 3. Changes over time in concentrations of IgG in the whole cohort, and IgM, IgA, and neutralising antibodies in an enriched comorbidities cohort were appropriately analysed using mixed effects models that accounted for repeated testing of individual participants over time.

As might be expected from past trials of COVID-19 vaccines, immunological findings showed that moderate titres were induced in response to the first vaccine dose, which subsequently boosted to high concentrations 1 week after the second dose. Firstdose immune responses were substantially lower in participants aged 66 years and older, and participants with immune suppression. Additionally, although the second vaccine dose did increase antibody titres substantially, they remained lower in individuals aged 66 years and older (vs younger individuals aged 18·00-65·99 years), males (vs females), obese individuals (body-mass index [BMI] ≥30 kg/m² vs BMI <25), and individuals with diabetes, cardiac disease, hypertension, and autoimmune diseases (vs healthy individuals). The findings are consistent with studies from other groups who found reduced immunogenicity from a single dose in high-risk groups. [3] [4] [5] In applied sciences, empiricism trumps reductionism. Dissecting a butterfly will not teach us how it flies, but observing it in flight will. Similarly, measurement of vaccine effectiveness depends not only on immunogenicity studies, but also on empirical evidence generated within efficacy trials, followed by careful observation of disease incidence following widespread use of the vaccine. Such post-licensure studies do indeed show protection among older adults and those with comorbidities. [6] [7] [8] [9] Given these observations, and given that even low titres of neutralising antibodies might suffice for protection against severe disease, 10 it might be tempting to discount Lustig and colleagues' findings 2 of lower immunogenicity in high-risk groups. We would be wiser, however, to note their implications.

First, widespread vaccination leads to transmission reduction, which in turn serves to protect unvaccinated and immune-compromised individuals. 11 High vaccine coverage protects a community, not just the vaccinated individuals, and although effectiveness studies might note disease reduction in all groups-a welcome outcome to be sure-ongoing individual vulnerability might be masked. Immunogenicity lacunae in individuals with co-morbidities, immunosuppression, or immune senescence should be documented, as Lustig and colleagues' study does, since the protection of these individuals depends on maintaining high population vaccine coverage, especially in case protective immunity wanes or vaccine escape variants emerge over time.

Second, vaccine policy should be based on robust science and lucid observations. Achieving higher coverage by wider distribution of available doses, at the expense of longer intervals between the first and second doses has been implemented in some countries such as the UK. Availability of evidence for the efficacy of this approach varies by vaccine type. As long as COVID-19 vaccine doses remain globally scarce, optimal allocation that maximises the total utilitarian good while remaining sensitive to distributional justice is challenging. Large-scale population-based randomised trials are being considered to evaluate the optimal interval between the first and second vaccine doses. Such trials are to be encouraged, but one should be mindful that the efficacy of such approaches might differ between risk groups. The evidence from Lustig and colleagues 2 argues for timely inoculation of the second dose for individuals at greater risk. Although population Comment www.thelancet.com/respiratory Vol 9 September 2021 943 benefits might be maximised through large-scale evidence generation regarding dosing intervals, there is merit in examining the optimal timing of boosting in special populations. Third, we should remember that vaccination is only one of the tools we have to protect against infection. Globally, where vaccine rollout has to occur in phases, individuals at risk should be prioritised for vaccination and receive both doses of a regimen, a lesson well highlighted in this Article. And until incidence declines substantially, ongoing non-pharmaceutical interventions such as masking will remain imperative.

Fourth, given the differences in immunogenicity between subgroups observed in Lustig and colleagues' study, long-term follow-up studies to evaluate immunological waning and memory cellular responses should be undertaken in different contexts, as results are also likely to vary with different vaccines.

Last, predictive forecast models have been influential in policy making during this pandemic; however, they are, of course, limited by their foundational assumptions. Models might be "always wrong but sometimes useful", 12 but little thought is given to what defines 'sometimes', or under what circumstances might empirical evidence of vaccine effectiveness lead to erroneous assumptions. 12 The relevance of reduced immunogenicity in vulnerable groups, even if this effect is masked by studies of population effects of vaccination, could be borne in mind when building predictive models and for future scenario modelling.

What matters is what we ought to do given what we know and have observed. The findings from Lustig and colleagues matter because they remind us not to ignore what we know about individuals when considering the meaning of what we observe in populations. When building models, making policies, planning evaluations, or interpreting data, maintaining these levels of perspective will help us to achieve the effectiveness we seek and the benefits that we are after.

NB-Z has received investigator-initiated research grants from Merck and the Serum Institute of India. AS has received investigator-initiated grants from Pfizer and the Serum Institute of India. 

Signals of hope: gauging the impact of a rapid national vaccination campaign

BNT162b2 COVID-19 vaccine and correlates of humoral immune responses and dynamics: a prospective, single-centre, longitudinal cohort study in health-care workers

Weak immunogenicity after a single dose of SARS-CoV-2 mRNA vaccine in treated cancer patients

Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study

BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting

FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multistate health system

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study

Effects of BNT162b2 mRNA vaccine on Covid-19 infection and hospitalisation among older people: matched case control study for England

What level of neutralising antibody protects from COVID-19? medRxiv 2021

Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers-eight US locations

Empirical model-building and response surfaces

As COVID-19 evolved in early 2020, several crucial issues for public health became apparent, including the need to reduce pressure on secondary care through effective treatment in the community for those at highest risk of hospital admission. PRINCIPLE, which began in April, 2020, was designed to test multiple therapeutic candidates efficiently using a master protocol within a platform trial. 1,2 In The Lancet Respiratory Medicine, Christopher Butler and colleagues 3 report the findings of one of the possible treatments for COVID-19; a relatively cheap and safe antibiotic doxycycline, for which community prescribing increased early in the pandemic. 4 This trial aimed to assess the efficacy of doxycycline to treat suspected