Covid-19 vaccine: fourth widespread dose? Initially, not

Fourth dose no. It’s what they said European Medicines Agency (EMA) and the European Center for Disease Prevention and Control (eCDC) in a joint statement posted a few days ago.

It is not a definitive “no”. Not an absolute “no”. Both agencies maintain the “fourth dose” recommendation (second booster dose) in immunocompromised individuals who may produce suboptimal responses to previous doses. Nor is it for security reasons. It is simply that there is not enough evidence to recommend the second booster.

Evidence on the effectiveness of the “fourth” dose

Most of the (limited) evidence on the fourth dose in the general population comes from a study with databases in Israel and in period of dominance omicron. In unadjusted results, the fourth dose, administered 4 months after the third and compared to people with only the third dose, reduces infections (17.7 vs. 36.1 cases of infection per 10,000 person-days of follow-up). and severe cases (0.15 vs. 0.39 severe cases per 10,000 person-days of follow-up).

But the protection against infection appears to be fading rapidly, and the protection against severe disease has been followed for only a few weeks. In addition, the study has some limitations to be able to generalize its results to other contexts:

1. Only mRNA vaccines have been used in Israel – for the full regimen and the first booster. There is no information for other vaccines used in Europe. Especially for the guidelines with adenovirus vaccines (AstraZeneca, Janssen).

2. The study is limited to the population aged 60 and over and excludes people who had suffered a SARS-CoV-2 infection. This exclusion in our context could leave out between a third (registered infection) and half or more (real infection) of the population.

3. It is not a randomized study and, despite being well conducted, it cannot guarantee that the people who voluntarily received the fourth dose were similar to those who did not receive it (control group), including differences in morbidity or risk behaviors. People who get vaccinated (or take the treatments) tend to have, on average, healthier behaviors than those who don’t. This effect, known ashealthy user bias” tends to overestimate the effectiveness of treatments in nonrandomized studies.

An second Israeli study, now in healthcare workers (without elderly or vulnerable population), suggests a low additional effectiveness against infection of the fourth dose compared to the third. 25.0% of the workers in the control group (three doses) became infected, compared to 18.3% of those who received a fourth dose with BNT162b2 (efficacy of the fourth dose compared to the third: 30%) and the 20.7% of those who received a fourth dose with mRNA-1273 (efficacy relative to the third: 11%).

As is usual in vaccinated young adults, most cases were asymptomatic or paucisymptomatic. But the viral loads were similar in both groups. The authors concluded that “a fourth dose of vaccine in healthy young health workers may have only marginal benefits”. Safety concerns with the fourth dose were not detected in any of the studies.

The epidemiological situation in Europe and Spain

Although the incidence rates of SARS-CoV-2 infection continue to be very high in many European countries, including Spain, the incidence of serious cases (hospitalizations, ICU admissions, deaths) remains modest (see Figure).

These figures, those offered by the usual statistics, refer to the entire population. But severe cases come mainly from people over 60 years of age and are much lower in immunocompetent young adults. It is more than doubtful that generalizing the “fourth” brings great additional advantages.

There are also no signs that, in people between 60 and 80 years old, the protection provided by third doses is fading in Europe and they need a “fourth”.

In addition, Europe is heading for good weather. And in good weather people spend more time outdoors. Although it is not obvious that the coronavirus has –or will have in the future– seasonal behavior, respiratory viruses tend to transmit worse in summer. It does not seem, at least for now, that the “fourth” are urgent.

The “fourth” in the world

With the little evidence available, and beyond the general agreement on administering it to immunocompromised patients, different countries have offered partially different responses.

Israel was a pioneer, offering as early as December the 4th dose to those over 60 years of age and health professionals who had received the third dose at least 4 months earlier. It did not save them from a very harsh omicron wave with a peak at the end of January (see Figure). But maybe something would help.

The United States, based on the Israeli studies, recommended the fourth for people over 50 years of age. In Latin America, Chile administers them to those over 55 years of age. Peru to those over 70. Argentina to those over 50 previously vaccinated with Sinopharm. In Brazil, for people over 80.

In Europe, the United Kingdom approved the “fourth” for people aged 75 and over. Sweden for those 65 and over. Other countries have done it for those 80 and over. And many others, including Spain, do not recommend it beyond specific groups. At the other extreme, Hungary does not set age limits, although the administration of the second booster must be assessed by a doctor.

It is what has the uncertainty. The limited evidence on the effectiveness of the “fourth” translates into different interpretations. The effectiveness of vaccines, the epidemiological context and other aspects. And the different interpretations lead to different booster dose policies. But, age cut-off points with years above or below, it is worth noting the uniformity in the recommendation of the “fourth” for immunocompromised.

Delay the “fourth” dose… but with an eye on epidemiological changes

There are several arguments to delay the “fourth” if the epidemiological situation does not require resorting to them. The virus has been changing. Vaccines don’t. All vaccines have been developed against the original Wuhan variant. And in these last two years a lot of time has passed and SARS-CoV-2 has made good use of it. More of the same could have much less value against the latest and future variants. But developing new – and better – vaccines takes time.

Some immunologists also point out that the repetition of the same vaccines, so close in time, could lead to a certain specialization and fatigue of the immune response. In any case, it does not seem reasonable to administer a vaccine whose marginal effectiveness is presumed minimal. For costs. For unnecessary. And because other countries still need those vaccines. Countries where effectiveness is far from marginal.

But the recommendations of the EMA and the eCDC have now been realized. In the current epidemiological context and with current evidence. And they serve only as long as the circumstances do not change and the scientific evidence does not provide more information.

New variants, fading immunity, increased gravity, or other circumstances may require “fourths.” Perhaps only for some groups. Perhaps, quite the opposite. Perhaps new evidence will lead us to discard them definitively.

If we have learned anything during the pandemic, it is to adapt public health strategies to each specific situation and to scientific knowledge. That should be the basis for current and future decision-making about the fourth dose. At the moment, too early for “fourths”.

Salvador PeiroResearcher, Health Services Research Area, FISABIO PUBLIC HEALTH, Phisabio

This article was originally published on The Conversation. read the original.