The only effective way out of the ongoing coronavirus disease 2019 (COVID-19) pandemic appears to be achieving population immunity by mass vaccination campaigns. These are aimed at eliciting immunity to the causative agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Evidence is piling up that the available vaccines do reduce the incidence of severe and critical COVID-19. Still, the question remains as to their ability to reduce case rates, viral shedding and transmission. An interesting new study by researchers at Harvard T.H. Chan School of Public Health in the U.S. suggests that the currently used Moderna vaccine reduces viral shedding by about 60%.
The researchers have released their findings as a preprint on the medRxiv* server.
Vaccine efficacy data
Information on the differential effect of the vaccine on infection and shedding is crucial in shaping public health policies regarding the level of social interaction permissible for those who have been vaccinated, the order in which vaccination should be applied, and the overall impact of vaccination.
This has not been addressed by randomized controlled trials (RCTs), which have largely dealt with the vaccine's ability to reduce symptomatic infection. This endpoint was determined largely because of the high morbidity and mortality rates experienced by many developed countries at the time of vaccine development.
How a vaccine affects transmission is a composite effect, made up of both its impact on new infections and on infectiousness. Uninfected individuals cannot transmit an infection to others, while those who are infected can and do. If infection is possible despite vaccination, the latter scenario holds good.
The researchers in the current study distinguish these two possibilities as vaccine efficacy for susceptibility to infection, and vaccine efficacy for infectiousness, respectively. They simulated the results from prior RCTs, in which participants were tested for viral shedding from the upper respiratory tract, independent of symptoms, to understand the prevalence of infection following vaccination.
The prevalence of viral shedding in vaccinated individuals tested at random would indicate vaccine efficacy against infection and the effect of reduced duration of infection quite reliably, almost like the method used earlier for bacterial shedding. It would yield a result at the lower limit of efficacy against viral transmission.
Simulation-based on actual data
The simulation included the follow-up of 100,000 individuals for 300 days, with a probability assessment for infection of each individual each day. Different probabilities of infection were simulated. Also, varying scenarios were implemented, from one where the individual became susceptible again immediately after recovery, to one where the recovered individual is assumed to be fully immune for the study duration.
Differing symptomatic case fractions were also used, assuming symptom onset at five days from infection, and viral shedding in infected individuals beginning three days from infection, for anywhere lasting from 15-21 days.
On day 100, half the individuals were randomly assigned to a prime-boost vaccination regimen, with a four-week interval between doses. The vaccine is assumed to have 50% of intended efficacy from seven days after the first dose, and 95% efficacy in reducing symptomatic disease at seven days after the second dose.
Vaccines that reduce both the incidence of infection and period of viral shedding during asymptomatic infection despite vaccination protect against viral carriage by a measure equal to the product of these quantities. This in turn would impact viral transmission to at least the same extent.
Thus, if a single cross-sectional swab sample is tested, according to the simulation, these methods closely reflect the simulated results in terms of the number of viral positives, which shows a clear downward dip immediately after vaccination, and lasts for a long period.
Moderna data analysis
In the published Moderna vaccine RCT, all participants underwent polymerase chain reaction (PCR) for SARS-CoV-2 at the time of the second dose. There were 39 and 15 viral positives in the placebo and vaccinated group. This would imply a vaccine efficacy against viral positivity of 61%.
When the researchers examined the data from this trial, they found that the number of people tested at this time point, in the modified intent-to-treat group, was not reported. They therefore assumed it included everyone who had not been infected by this time.
If so, the vaccine efficacy against viral positivity after one dose would be underestimated. Some of these could have been infections acquired before the first dose, however. Secondly, if the test included only viral carriers and non-infected participants, the first group might include many vaccinated individuals in whom the vaccine contributed to asymptomatic infection.
Both these factors could contribute to falsely low estimates of vaccine efficacy against viral positivity. If so, the researchers conclude, "the Moderna data from the second-dose swab provides evidence of at least a 61% reduction in transmissibility due to a single dose of Moderna vaccine."
As such, the simulated vaccine estimate obtained by combining symptom-dependent testing and testing of all cases is about 90%, which underestimates the actual estimated accuracy of 94%.
What are the implications?
In order to improve vaccine efficacy measures, the researchers recommend symptom-independent sampling of a cross-section of the vaccinated population as well as the control group on the same day. If not, the combination of viral positives obtained by testing symptomatic infected subjects as well as screening asymptomatic (infected or non-infected) participants leads to a vague mix of vaccine efficacies against viral positivity and symptomatic infection.
An exception to this is if cross-sectional sampling is restricted to non-symptomatic infections, in which case the number of symptomatic patients would be heavily biased towards the control group. This would underestimate the actual vaccine efficacy against viral positivity.
The study thus presents an improved approach to the analysis of vaccine trial data, classifying tests in those who are symptomatics from those carried out for routine screening. The latter group itself is divided into those who are tested because they might have been exposed, and those tested for other purposes such as before travel.
The symptomatic group tests will yield the incidence rate, while the exposure-test group will provide the secondary attack rate. The third group will be best analyzed following the approach in the current study, say the investigators.
They point out that a useful proxy for vaccine efficacy against transmission, in practice, would be to consider the estimated effect of the vaccine against viral positivity as the lower limit of the former measure.
Such analysis can allow the quantification of vaccine efficacy against viral positivity, and thus in reducing transmission. In the future, viral load quantification in these groups could allow more accurate estimates of vaccine efficacy in both areas.
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.