- Transmission measure key in person exposed to virus, not in infected, vaccinated person
- mRNA vaccines may have transmission impact edge due to antibody-skewing MOA
- 50% vaccine efficacy benchmark used by regulators inappropriate for use in transmission
Covid-19 vaccines developers’ ability to demonstrate transmission reduction based on decreases in infection rate provoked varied expert analyses. It could be surmised that if a vaccine reduces the number of infection events, including asymptomatic disease, then this could be a surrogate for transmission reduction, some said. However, others were not as optimistic, noting this correlation is not direct or that transmission rate analysis should be based on how likely it is for an exposed, nonvaccinated person to be infected by an infected, vaccinated individual.
Talk of Covid-19 vaccines’ potential to reduce transmission reached a fever pitch in the past few days, with the release of more data on both authorised and yet-to-be-sanctioned vaccines. As countries grapple with the pandemic, they are looking for glimmers of hope that the vaccines can also reduce transmission and bring a quicker end to lockdown measures. Among the frontrunners, the University of Oxford and AstraZeneca have pointed to infection event reduction as a possible surrogate for transmission, while Johnson & Johnson revealed asymptomatic data yesterday (24 January) but called it exploratory. Pfizer/BioNTech’s Comirnaty (BNT162b2) also drew worldwide interest due to Israeli news media reporting on the vaccine’s potential to prevent transmission based on data collected from the local vaccination campaign.
However, interviewed experts expressed a range of sentiments on whether infection rates could be used as a surrogate for transmission reduction: two said asymptomatic and symptomatic infection events are a fair surrogate; two others were less sure and wanted more data to detail correlation or to be coupled with an analysis from nonvaccinated individuals; while a fifth expert voiced concern over conflating infection rates with transmission rates.
Nevertheless, all experts agreed the 50% benchmark for Covid-19 vaccine efficacy should not be applied to transmission, as this yardstick lacked scientific rationale when it was established. Regardless of what transmission data is reported, there is the need to vaccinate as much as two-thirds of a specific community before thinking about easing social distancing and mask wearing, as these two measures supplement vaccines in preventing transmission, noted Dr Maria Elena Bottazzi, associate dean, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas.
Experts agreed that measuring transmission rates directly is logistically challenging. Viral load measurements, though, is a possible efficacy measure and one that would be better than using duration of infection.
The aforementioned companies and institutions did not respond to a comment request.
Two perspectives on measuring transmission
If a Covid-19 vaccine can reduce SARS-CoV-2 infection events, asymptomatic or otherwise, this may signal that virus transmission to others could be reduced, said Bottazzi. That theory is based on the thinking that when there are fewer people infected with the virus, then there are fewer people spreading the virus, she explained.
Yet Nikolai Petrovsky, PhD, professor, College of Medicine and Public Health, Flinders University, Adelaide, Australia, differed, noting a vaccine’s ability in reducing infection is a questionable surrogate for transmission reduction. Transmission should be measured based on the nonvaccinated person who is exposed to SARS-CoV-2, and not based on the vaccinated, infected person potentially transmitting the virus, he explained. “Transmission is about the next person in the chain,” Petrovsky said, adding that infection rates and transmission rates should not be conflated.
While there may be association between infection and transmission, there is insufficient data to assess if there is a linear correlation, said Gary Kobinger, PhD, head, Vector Design and Immunotherapy Special Pathogens, Medical Microbiology, University of Manitoba, Canada. Indeed, vaccine transmission efficacy is critical to be measured in those who are not vaccinated but exposed to the virus, but there is also value in collecting data from the virus spreader, added Rory de Vries, PhD, assistant professor, Department of Viroscience, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Transmission reduction benchmarks unclear
Directly measuring transmission reduction is challenging, so perhaps the best option is to infer data from infection prevention, added Stanley Perlman, professor, Department of Microbiology and Immunology, University of Iowa. While experts differed if infection and transmission correspond to each other, they all agreed the current 50% benchmark for vaccine efficacy should not be applied to transmission. In fact, they were hesitant to establish a benchmark due to the inherent challenges in measuring transmission. In vaccine development, the benchmark is typically around 75% efficacy, but various regulatory agencies lowered this to 50% for Covid-19, because it was then unclear if SARS-CoV-2 would be susceptible to vaccines, Petrovsky explained.
AstraZeneca has noted that its infection risk data could be a potential surrogate for transmission reduction. In the UK-based Phase II/III AZD1222 trial (NCT04400838), a single dose has 63.9% efficacy against asymptomatic or symptomatic infection (Voysey M, et al., Lancet. 2021 Feb 19; S0140-6736(21)00432-3). Johnson & Johnson states that its results on asymptomatic infections are exploratory, but JNJ-78436735 has an 87.8% efficacy in preventing asymptomatic or undetected infections, according to its briefing document for tomorrow’s (26 February) FDA advisory committee meeting. And Israeli media has suggested transmission reduction with Pfizer’s Comirnaty based on observational effectiveness data of 92% versus an infection event (Dagan N, et al., N Engl J Med. 2021 Feb 24. Doi: 10.1056/NEJMoa2101765).
Between mRNA and adenovirus-vectored vaccines, the former may have the edge in preventing transmission as they work more upstream of the SARS-CoV-2 life cycle, noted Petrovsky. mRNA vaccines are more geared towards initiating a Th2 immune system response, which leads to the proliferation of antibodies that prevent the virus from entering the host cell, thus blocking viral replication earlier, he explained. In contrast, adenovirus-vectored vaccines lean towards triggering a Th1 response, which triggers cytotoxic T cells to attack host cells that already carry the virus, he added. Comirnaty and Moderna’s mRNA-1273 are mRNA vaccines, while AZD1222 and JNJ-78436735 are adenovirus-vectored vaccines.
Viral load more critical measure than infection duration
While Covid-19 vaccines have yet to report clear transmission data, they do have results showing they can prevent vaccinated, infected people from developing more severe disease, noted Bottazzi. Severe patients have higher viral load, while asymptomatic patients have lower levels, added de Vries. However, it is still unclear what viral load level makes a person most infectious, Bottazzi said.
With regards to transmission, viral load is key, rather than the stage of disease, Bottazzi said. Even if a vaccine can reduce a person’s infection from 14 days to a week, for example, this would be an inappropriate surrogate for reduced transmission, Petrovsky added. Infected people are most infectious between days 4 and 6, Kobinger noted, therefore reducing infection days is irrelevant in terms of transmission reduction, Petrovsky explained.
Additionally, testing can be inconsistent or sporadic such that a person’s infection could be missed, specifically asymptomatic patients, Petrovsky noted. The Lancet paper noted AZD1222 volunteers were tested once a week. In the Comirnaty observational trial, vaccinating 1.5 million people, participant follow-up ended after an outcome event like symptomatic disease or end of the study period. Infection events were monitored up to day 42 of the first dose.
Vaccines need to reduce viral load in the upper and lower respiratory tract to demonstrate transmission prevention, Petrovsky added. If a vaccine can reduce viral load in the lungs—such as may be the case in asymptomatic disease—the viral load could still be high enough in the nose, he added. Coughing and sneezing allows spread of virus particles from the lower respiratory tract, explained Matthew Meselson, professor, Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts. Normal breathing allows for aerosols to carry virus particles from the upper respiratory tract, he added.
The best way to demonstrate prevention of transmission is post-authorisation analysis in households, where one person has been vaccinated and others in the same house are monitored for infection, Perlman said. The caveat is that nonvaccinated people could acquire the virus from outside the household, he added. This could be replicated in human challenge trials, but while the UK has allowed for such a study to proceed, the ethical questions around this approach are not diminished, de Vries noted.
Perhaps animal models may be a good way to demonstrate prevention of transmission, Petrovsky said, adding transmission can be measured between a vaccinated, infected animal subject and other subjects. Ferrets are ideal Covid-19 vaccine models, because their respiratory tract is comparable to humans, and they are susceptible to SARS-CoV-2, de Vries explained. Available preclinical data from the various authorised Covid-19 vaccines focuses on viral load reduction.
Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.