Delaying Second Doses of COVID-19 Vaccines Has Benefits, but Effects Depend on Immunity

"Several countries, including the United Kingdom and Canada have stated that they will delay second doses of COVID-19 vaccines in response to supply shortages, but also in an attempt to rapidly increase the number of people immunized," explains Chadi Saad-Roy, a graduate student in the Departments of Ecology and Evolutionary Biology (EEB) and Quantitative and Computational Biology in the Lewis-Sigler Institute at Princeton and the lead author of the study.

"The original clinical trials of the vaccines, plus subsequent epidemiology, are quite optimistic regarding the efficacy of the first dose. However, we are still uncertain how the strength and duration of immunity from a single dose (or the full two-dose course or natural infection, for that matter) will persist in the longer term," adds Saad-Roy.

The researchers used a simple model to project forward the incidence of COVID-19 cases, as well as the degree of immunity of the population, under a range of vaccine dosing regimes and assumptions related to immune responses. "Given the immunological and epidemiological uncertainties driving these outcomes, simple models are an essential tool to explore future possibilities," says Caroline Wagner, an assistant professor in the Department of Bioengineering at McGill, and the senior author on this paper.

The study found that one-dose strategies may, as expected, reduce case numbers in the short term by more rapidly immunizing a greater number of individuals. However, if immune responses after one dose are less robust, subsequent epidemic peaks may be larger.

"More optimistically, we find that as vaccine capacity increases, increasing vaccination rates or changing the dosing regime to closer to the recommended two-dose schedule can mitigate these longer term epidemiological effects, which is important for public health planning," adds Wagner.

Another important outcome associated with imperfect immune responses is the potential for viral immune escape. To start addressing this complex issue, the authors adapted a previous simple 'phylodynamic' model for viral immune escape, developed by co-authors Bryan Grenfell, Oliver G. Pybus, and Edward C. Holmes, along with other colleagues not involved with the current work. This theory predicts that in individuals with partial immunity, moderate selection pressure combined with sufficient viral transmission could drive evolution. Here, the authors explore this possibility along with a range of other scenarios, including the more optimistic case of minimal potential for adaptation in hosts with waned immunity following one or two vaccine doses.

"At least one variant has already emerged that may be adapted for partial immune escape," notes Holmes. "Simple theory underlines that the evolution and transmission of variants by infected hosts with intermediate levels of immunity may be important. Therefore, the strength and duration of immunity, and particularly the effect of these on retransmission, are key parameters to determine" adds Grenfell.

One intuitive finding that the paper emphasizes is that very low rates of vaccine administration may be associated with larger case numbers and, possibly, more elevated potential for viral adaptation. "This strongly underlines the importance of equitable global vaccine distribution, as immune escape in one location will rapidly spread," explains C. Jessica E. Metcalf, a co-author on the paper, and an Associate Professor in EEB and the School of Public and International Affairs at Princeton and an associated faculty member at the High Meadows Environmental Institute.

"The models are relatively simple conceptually, but they illustrate the complexities of the problem and highlight the challenges that we still face," notes Michael Boots, a Professor of Integrative Biology at UC Berkeley who was not affiliated with the present study. "This important piece of work provides a framework that we can use to inform our approach going forward and moreover identifies the key knowledge gaps that we need to address," adds Boots.

The article, "Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes," by Chadi Saad-Roy, Caroline Wagner, et al., was published in Science.

The study was funded by the Natural Sciences and Engineering Research Council of Canada, the Cooperative Institute for Modelling the Earth System at Princeton University, the James S. McDonnell Foundation, the C3.ai Digital Transformation Institute and Microsoft Corporation, Google, the National Science Foundation, the US Centers for Disease Control and Prevention, and Flu Lab.

Source: McGill University

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