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Fourth COVID-19 vaccination superior to third against adverse COVID-19-related outcomes

A fourth COVID-19 vaccination offers greater protection against adverse COVID-19 outcomes compared to individuals having had only three doses

Having a fourth COVID-19 vaccination at least four months after the third dose, offers better short-term protection against COVID-19-related adverse outcomes compared to only three doses of the vaccine. This was the main finding of a study by Israeli researchers from the Clalit Research Institute, Innovation Division, Tel-Aviv, Isreal.

Whilst millions of individuals have now received at least three doses of a COVID-19 vaccine, there is evidence that with the emergence of variants such as Omicron, vaccine effectiveness wanes over time. This was observed, for example, in one US study, during the Omicron period.

The authors found that vaccine effectiveness against emergency department visits was 87% during the first 2 months after a third dose but decreased to 66% among those vaccinated 4-5 months earlier. In fact, it is already apparent, albeit from a single study, that the rates of confirmed COVID-19 infection and severe illness were lower after a fourth dose of BNT162b2 vaccine compared to after only three doses.

Whilst this is an important finding, to date, the effectiveness of a fourth COVID-19 vaccination against other outcomes of interest such as hospitalisation and deaths remains uncertain.

For the present study the Israeli team examined the relative effectiveness of four compared to three doses of vaccine among those aged 60 years and older who had received a third dose at least 4 months earlier.

Using data contained within the Clalit Health Services, which is the largest payer-provide organisation in Israel, the team included patients deemed eligible for a fourth dose and who had no previously recorded infection with COVID-19.

There were a total of 5 outcomes of interest: COVID-19 infection; symptomatic COVID-19, COVID-19-related hospitalisation, severe COVID-19 and COVID-19-related death. All of these outcomes were assessed 7 to 30 days after the fourth COVID-19 vaccination and 14 to 30 days after vaccination. Those who received a fourth vaccine dose were matched with individuals who had only received three doses and with similar co-morbidities.

Fourth COVID-19 vaccination and adverse COVID-19-related outcomes

A total of 182,122 individuals who received a fourth vaccination dose and a median age of 72 years (53% female) were matched with a group of control patients (three vaccine doses).

During days 7 to 30, the estimated relative effectiveness of the fourth COVID-19 vaccination compared to three doses was 45% against a PCR confirmed COVID-19 infection, 55% against symptomatic COVID-19, 68% against COVID-19 hospitalisation and 74% against COVID-19-related mortality. Moreover, these effectiveness values were broadly similar when assessed 14 to 30 days after the fourth dose.

The authors discussed how use of a fourth dose appeared to be effective against the Omicron variant which was the main circulating variant at the time of the study (January 3 to February 18, 2022). They concluded that a fourth COVID-19 vaccination dose provided additional protection compared to only three doses in those older than 60 years of age.

Magen O et al. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting New Eng J Med 2022