An interesting new preprint on the medRxiv* server shows that even if countries are forced to delay the second dose of the current vaccines administered against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to arrest the ongoing coronavirus disease 2019 (COVID-19) pandemic, the cumulative mortality would still fall significantly.

The study aimed to provide an in-silico estimation of the health outcomes in the population, given either as originally scheduled or with a delay in the administration of the second dose.

Vaccine contenders

The earliest vaccines to gain emergency use authorization in the USA were the two messenger ribonucleic acid (mRNA) vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna). These are meant to introduce the mRNA encoding the spike antigen of the virus.

A third vaccine approved in the UK and most of Europe is based on the chimpanzee adenovirus (ChAdOx1) viral vector vaccine (Oxford-AstraZeneca).

The first two were developed and marketed as two-dose vaccines, with the second or boost dose coming 21 and 28 days from the first or prime dose, respectively, as per the manufacturer’s instructions.

Simultaneously with vaccine roll-out, new and potentially more dangerous variants of the vaccine, such as the B.1.1.7 (UK), B.135 in South Africa and P.1 in Brazil, have emerged. Particularly with the second of these, there is evidence that these strains confer partial vaccine resistance, as well as higher transmissibility and perhaps even more virulence.

Wide coverage, reduced mortality

The most effective way to counter the rapid spread of these new variants is to ensure the widest possible vaccine coverage as soon as possible, thus raising a wall of immune individuals around the currently infected people to limit the spread of the virus.

A serious challenge in this regard is the shortfall in the supply of the vaccine, hampered by inadequate manufacturing facilities, refusal to make vaccine production information public or to franchise it, and logistical difficulties with maintaining a cold chain over vast distances.

Single-dose vaccine

Based on available observations, many public health authorities have concluded that giving a single dose of the vaccine to the greatest possible number of people could spread the vaccine net wider, rather than ensuring that all those who receive the first dose also get the second within the stipulated interval.

The assumption that a single vaccine dose can provide substantially effective protection is, however, highly controversial. Moreover, the fact that the clinical effect of two doses with the second dose being given after the stipulated interval was not studied in the clinical trials of these vaccines has raised considerable doubt as to whether they should be administered in this manner.

The vaccine's ability to reduce asymptomatic transmission was also not a subject of investigation in these clinical trials.

On the other hand, taking what is already known about vaccine immunology encourages the view that the single-dose assumption is valid, and clinical trial data on the Pfizer and Moderna vaccines has been re-analyzed to calculate the first-dose efficacy.

The high figure of around 92% has led to the suggestion that a delayed second dose protocol be adapted to solve these issues and reduce the cumulative mortality. Further modeling is then necessary to understand how this change in strategy can impact mortality, the transmission network, and the case fatality rate, which can be at least two orders higher depending on the demographic group.

The current study used agent-based modeling (ABM) for this purpose, comparing the rates of infection, hospitalization and mortality with standard and delayed second dose policies.

Varying efficacies with medium vaccination rates

The simulation results show that at a vaccination rate of 0.3%, cumulative mortality for the standard and delayed second dose strategies at three different values of first-dose efficacy, from 70% to 90%, is comparable or lower. With higher estimated efficacy, the cumulative mortality falls. When it is at 70%, the difference is insignificant.

At 90%, it falls from 226 with standard-dose regimens to 179, and at 80%, from 233 to 207.

Cumulative infections per 100,000 are not significantly lower with the delayed dose regimens at all three efficacies.

Efficacy fixed at 80%

Secondly, if the vaccination rate is altered between 0.1%, 0.3%, or 1% per day, with an estimated single-dose efficacy of 80%, the population death rate would be lower with a delay in the second dose in all cases unless the vaccination rate was extremely high.

Since the current vaccination rate in Europe is 0.1% per day, this suggests that a delayed second dose plan is suitable to reduce the total mortality.

Delayed except for 65+

If standard second dose schedules are given to those above 65 years, who have an estimated ten-fold higher mortality and a weaker immune response, with others receiving a delayed second dose, the total death rate is lower than with the standard second dose regimens.

Not only is the “delayed except for 65+” plan more effective than the standard schedule at low and medium vaccination rates, but cumulative mortality with this approach, at a high 1% vaccination rate, is even less than with the delayed second dose strategy for everyone.

If the vaccine is assumed to prevent only symptomatic infection, the cumulative mortality with the delayed second dose strategy is still almost ideal if the vaccine efficacy is 70% or more, at medium vaccination rates of 0.3% per day.

What are the implications?

This time-bound simulation study shows that vaccination rates are key to determining the optimal vaccination strategy to reduce cumulative mortality as much as possible. At high vaccination rates of 1% a day, delayed doses are not associated with significant mortality benefits.

Similar is the case at low vaccination rates. However, with medium rates of vaccination, such as those seen in the USA at present, delaying the second doses except in those over 65 years is associated with a favorable result.

The benefits are confined to mortality, without a significant reduction in infection rates.

Such information should help to promote delayed second dose strategies that could vastly extend vaccine coverage. A large number of subjects over a range of ages, and various interaction networks, in this simulation, helped to mirror human behavior in the real world. The period of 180 days chosen for this model was to facilitate its application to the current scenario. The challenge is to boost population immunity without a dramatic rise in vaccine production rates in the near future.

A delay in the second dose by up to six months is unlikely, based on current knowledge about vaccine-elicited immunity, to affect vaccine efficacy. This is supported by data from small studies on the delayed second dose administration of the Astra-Zeneca vaccine by 12 weeks or more, which has shown higher efficacy compared to the standard 21-day second dose schedule.

Delaying the second dose of either of these vaccines has been an appealing strategy because it would significantly increase vaccine availability and reduce the logistics of a strict two dose schedule. Hesitation regarding delaying a second dose is understandable given limitations of any study design that is not a randomized trial. However, our agent-based model can provide estimates of relative differences between these strategies that can be helpful in making policy decisions.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.