Are yearly shots in the works?
CLINICAL MATTERS
Do you need a fourth shot? When should you get one? What about a fifth shot? Is this going to be a yearly thing? The resurgence of Covid-19 as a result of breakthrough infections by the variants of concern has tempered expectations on the ability of vaccines to end the pandemic. While early transmission-blocking vaccine efficacy was very high for the early lineages of SARS-CoV-2, the virus quickly mutated, resulting in more and more breakthrough infections and dashing hopes of elimination.
As cases climbed in Israel in August 2021 with Delta, third doses of mRNA vaccines were quickly deployed among healthcare workers and were shown to restore some protection against infection. During the Omicron outbreak in the UK, there was a distinct drop in protection against infection without a booster. Newer data from Israel is now showing a significantly decreased risk of death for those who received a second booster four months after the first booster among those aged 60 years and older. This data is the basis for the US FDA recently approving a fourth dose for the elderly and immunocompromised in the US. Given the paucity of data, however, the US Centers for Disease Control says it is allowing the second booster for the same target population, but it is not requiring it at this time. When will all this end?
When the Covid-19 vaccine framework was first developed by WHO, there was a lot of uncertainty over the feasibility of developing a vaccine against a coronavirus. There had not been any successful vaccines developed for humans. The likeliest vaccine candidates were not able to proceed with phase 3 trials after the SARS and MERS outbreaks spontaneously terminated before large-scale clinical studies could be done.
Given the huge potential benefit of a working vaccine against a pandemic virus that was expected to infect millions, the initial cut-off for an acceptable Covid-19 vaccine efficacy against symptomatic infection was set at 50 percent by the World Health Organization.
Part of the reason this was the chosen endpoint was the rapidity at which efficacy could be assessed. Vaccines work in multiple ways: they can block transmission, they can block symptomatic infection, they can block severe disease and hospitalization, and they can prevent death.
The problem with assessing transmission-blocking vaccines is the difficulty of finding asymptomatic individuals early in the pandemic. Since RT-PCR tests at that time were still in short supply, only symptomatic individuals were prioritized for testing. It wasn’t clear what proportion of individuals was truly asymptomatic. As for severe disease, hospitalization, and death, these represent a smaller proportion of those infected overall, and a study looking at any of these three parameters as a primary outcome would take a long time to enroll enough patients. In contrast, a population where the symptomatic infection is the outcome of interest (whether mild, severe, or critical) is far easier to recruit and follow. It was therefore decided that vaccine efficacy among those with symptomatic infection was the most appropriate primary study outcome, while analysis of subsets of severe disease, hospitalization, and deaths from Covid-19 would be done as secondary outcome measures.
When the first vaccine efficacy trials came out in December 2020, scientists were pleasantly surprised to see that the Pfizer mRNA vaccine showed the efficacy of over 90 percent against symptomatic infection. This was shortly followed by the Moderna mRNA vaccine, which likewise showed an over 90 percent efficacy against symptomatic infection.
The next few vaccines did not show as high an effect, with the Astra vaccine showing a 60 to 80 percent vaccine efficacy against symptomatic infection in multiple trials, and Sinovac vaccine showing a 51 percent vaccine efficacy in Brazil among healthcare workers. All these vaccines did show over 90 percent protection against hospitalization and death. With a worldwide shortage in vaccines, many countries elected to use Chinese vaccines even as developed countries hoarded the ostensibly more effective mRNA vaccines.
When the Sinovac trials in Brazil were reanalyzed, it was theorized that the decrease in efficacy against infection was due to the predominance of the Gamma variant of concern in the country at the time of the study. When Sinovac was evaluated in countries where other lineages were prevalent, it was shown to be 70 to 90 percent effective against symptomatic infection. A prospective transmission-blocking study showed an approximately 60 to 70 percent efficacy in blocking asymptomatic transmission. This was lower than an up to 90 percent transmission-blocking efficacy for the mRNA vaccines with the old lineages, but these findings were still quite significant. The presence of a transmission-blocking component in vaccines was proof of the concept that SARS-CoV-2 could be eliminated with a high enough level of herd immunity.
When Alpha and Beta emerged in late 2020, there was a lot of concern about breakthrough infection. While Alpha ultimately proved susceptible to most vaccines, Beta showed a significant breakthrough infection rate, especially against the Astra vaccine. In one study, this was as low as 10 percent vaccine efficacy against preventing symptomatic infection in trials in South Africa. Protection from severe disease remained significant. Beta turned out to be a harbinger of more variants that exhibited higher reinfection rates and breakthrough infections.
When the Delta variant hit, the increased severity of the infection and higher viral loads resulted in higher hospitalization and deaths overall. Analysis of outbreak data, however, still showed high levels of protection from two shots of the vaccines, with a modest improvement in protection with a booster. Against this backdrop, the first boosters in the country for A1 (healthcare workers), A2 (seniors), and A3 groups (comorbid conditions) were approved even as the government continued to actively pursue primary series vaccination for the general public.
In December 2021, early vaccine efficacy data for mRNA vaccines with the rise of the Omicron wave showed that breakthrough infection was much higher compared to Delta.
A booster after three months from the second dose restored a significant level of protection from symptomatic infection and disease severity. Locally, boosters were quickly expanded to the general population of 18 years old and above and could be given as early as three months from the second dose. This was a much more aggressive time frame compared to other countries where the booster was delayed for five to six months. In retrospect, this aggressive boosting in December before the entry of Omicron may have significantly attenuated case numbers and hospitalization. Other factors contributing to a relatively tempered Omicron wave were discussed in last week’s column. So, do we need a fourth dose? The Philippine FDA is currently reviewing the data for this, and the Vaccine Experts Panel has given a favorable view on it for seniors and immunocompromised persons. It is unclear, however, if this applies only to mRNA vaccines or the other vaccine types as well. The timing of the second booster is still uncertain. Given the paucity of data, second boosters will probably be rolled out for immunocompromised and elderly individuals initially, similar to the US. Meanwhile, the uptake of a third dose/ first booster remains low.
First, boosters should be pushed further and should be administered while cases remain low as another layer of safety against potential Covid-19 future spikes. A fifth dose and beyond are still not supported by any data and may be attended by safety concerns. Giving too many boosters may paradoxically lower vaccine efficacy and pre-empt newer generations of Covid-19 vaccine that may be more efficacious. The first booster is recommended, and everyone above age 18 should take it as soon as possible. Beyond that, stay tuned and follow your doctor’s advice.