COVID-19 vaccine administered in mid January at the Jacob K. Javits Center in New York City, which has been converted into a vaccination site.

As COVID-19 cases are starting to spike around the world once again, a new study published in The Lancet Respiratory Medicine “provides safety assurances to the global population” about fourth vaccine shots.

The study, conducted in Israel, is the first large-scale research into the safety of the additional booster. It comes at the same time as two separate studies conducted in Thailand reaffirm the effectiveness of the additional booster against Omicron and the importance for high-risk individuals of taking any shot – regardless of the type of vaccine. 

As people become eligible for fourth (and in some cases fifth) shots of the COVID-19 vaccine, there has been increased reluctance, possibly because of previous side effects, but more likely because of the absence of sufficient vaccine safety information. 

In the United States, two months after the Centers for Disease Control and Prevention recommended a second booster, only 21.5% of eligible individuals had received the shot. Similarly, in Israel, where the research was conducted, fewer than 900,000 accepted the fourth jab, compared to more than six million who took the first three, despite its availability since the end of last year. 

Only 320,000 Israelis have taken the newly available Omicron-specific Pfizer vaccine.

Tel Aviv University’s Prof Dan Yamin, who led the research, said that the hope is that these safety assurances “can help increase the number of high-risk individuals who opt to receive this booster vaccine and thereby prevent severe outcomes associated with COVID-19.”

Dr Dan Yamin

No increase in side effects with fourth shot

Yamin and his team decided to evaluate the safety of the shot when they discovered there was a gap in the literature, he told Health Policy Watch. While regulatory authorities require large, controlled trials before approving a primary vaccine series, “when it comes to boosters, the regulations are that you don’t really need to show a safety profile in a large dataset.

“We wanted to check it out,” he continued, “and look at these safety concerns.”

In this study, Yamin’s team evaluated the safety profile of taking a second Pfizer COVID-19 booster vaccine using data from both a retrospective and a prospective cohort. The retrospective study looked at what vaccine side effects were reported by doctors and patients. For the prospective study, participants were equipped with smartwatches and the researchers evaluated both what they reported, and also objective, continual measurements being taken by the watches. 

The first part involved analyzing the anonymized medical records of 250,000 members of Israel’s Maccabi Health Services, the second-largest healthcare provider, to understand if there were any short-term “adverse events” from taking the second vaccine compared to taking the first. The team also evaluated if any of the 25 adverse events happened at all.

Of the 250,000 records received, 94,169 people received the first booster and 44,003 were eligible for the second. Of those who were eligible, 17,814 received the shot. Their age ranged from 18 to 104, with the median age of 69. 

“Comparing the 42 days before and after vaccination, the second booster was not associated with any of the 25 adverse events investigated, including myocardial infarction and Bell’s Palsy,” the researchers wrote in their paper. “None of the individuals was diagnosed with myocarditis or pericarditis following vaccination with the second booster.”

The most frequently reported reactions were fatigue, headache, muscle pain, cold and a sore throat. These reactions faded in nearly all participants within three days of receiving the second vaccine. 

Elevated heart rates 

But Yamin said the team did not stop there because sometimes patients experience side effects and may choose not to report them. 

“We tried to challenge the vaccine as much as we could,” Yamin said.

So, they recruited patients who consented to take part in the smartwatch study, so that they could monitor several physiological measures, including heart rate – something that individuals are unlikely to observe for themselves. In addition to the digital monitoring, the mobile application collected daily self-reported questionnaires on local and systemic reactions. 

Some 1,785 participants who received the first booster and close to 700 people aged 18 and older from across Israel who received the fourth shot participated in the study between 30 December 2021, and 22 July 2022. 

“We found no significant differences after inoculation with the first booster compared with the second booster” regarding most events, Yamin noted. That is, except on one data point, revealed by the smartwatches: Fourth shots did elevate average heart rates beyond the baseline — meaning the pre-vaccination rate. 

“We found a significant increase in mean heart rate relative to that observed during the week before vaccination levels during the first three days following the second booster, peaking on day two,” Yamin told Health Policy Watch. “Mean heart rate values returned to baseline levels by day six.” 

Similar trends were observed for other measurements, including HRV-based stress and resting heart rate, he said.

“Previous studies have suggested that even a minor long-lasting increase in heart rate is associated with an increased risk of death,” the authors wrote. “However, in our study, the daily mean difference of heart rate values returned to baseline levels by the sixth day after vaccination, so we do not expect an increased risk by this temporal change.”

Yamin said that an elevated heart rate for a few days after vaccination is not uncommon because when a person’s immune system is working hard, it can lead to a decline in heart rate variability as the body concentrates on the other tasks at hand. He said that from a clinical standpoint, the temporary elevated heart rate in 5 beats per minute observed is not really relevant.

However, he added that “what is clear is that the vast majority of people hospitalized are older and in a high-risk group. There is a vaccine that we found is safe and we highly recommend taking it based on these findings.”

Heterologous, homogeneous vaccines equally as effective

Nearly 7,000 kilometers away from Israel, in Thailand, a separate research team found that taking a fourth shot of any of the COVID-19 vaccines reduces the chance of infection by 75% compared to not taking any vaccine, while a third dose is only 31%.

“The vaccine effectiveness against Omicron infection was comparable across the AstraZeneca, Pfizer and Moderna boosters,” lead researcher Prof Suwat Chariyalertsak, dean of the Faculty of Public Health at Chiang Mai University, told Health Policy Watch.

Prof Suwat Chariyalertsak

Moreover, his research showed that a fourth shot taken less than 90 days before COVID infection provided as much as 4% greater protection than the third dose on its own.

The study drew on a unique active surveillance network established in Chiang Mai, located in Northern Thailand, with a population of 1.6 million. Nearly 100% of citizens received heterologous vaccine schedules – starting with one of the approved Chinese vaccines and then being eligible for additional shots with the AstraZeneca, Pfizer or Moderna COVID-19 vaccines.

In a paper published by The Lancet Regional Health – Southeast Asia, Chariyalertsak and team evaluated the vaccine effectiveness of heterologous third-dose and fourth-dose COVID-19 vaccine schedules during both the Delta- and Omicron-predominant periods. In other words, they tried to see if individuals were equally as protected if they took an AstraZeneca, Pfizer or Moderna booster shot in combination with a previous vaccine. 

They found that effectiveness against Delta infection was minimal after receiving only a single dose of vaccine. A two-dose primary vaccine series had vaccine effectiveness of 63% against Delta. A third dose increased the vaccine effectiveness to 97%.

Regarding Omicron, one or two doses of the vaccine provided little to no protection against Omicron, while three doses increased vaccine effectiveness to 31% and a fourth dose to 75%.

“The vaccine effectiveness of third or fourth doses against omicron infection was equivalent for the three main vaccines used for boosting in Thailand, suggesting coverage, rather than vaccine type is a much stronger predictor of protection,” the researchers wrote. 

No severe outcomes

Perhaps more importantly, Chariyalertsak said, in a separate paper published in the International Journal of Infectious Diseases, they found that severe outcomes were not observed among patients who received a fourth dose after a median of 53 days since the last vaccine dose. Patients who received the third dose 14 to 90 days before the date of testing positive for the virus had the highest risk reduction against severe COVID-19 outcomes – 93%.

“Our paper provides much-needed evidence to support the ongoing national efforts to increase population coverage of booster doses,” the researchers added.

Chariyalertsak said that in Chiang Mai only one or two people who received the fourth dose have entered the intensive care unit or died due to COVID-19. He added that an additional value to the study of a heterologous regime is that people who are hesitant to take an mRNA vaccine can feel confident taking one of the other varieties as their booster. 

“We really want people, especially those who are older or who have other comorbidities, to come for the booster doses – third, fourth or even fifth doses, if the last vaccine shot was longer than four to six months ago,” Chariyalertsak told Health Policy Watch. “Either a booster with a viral vector or mRNA will show the same effectiveness to reduce the severe outcomes and death during this time. 

“There is no need to wait for the future vaccine, such as the bivariant one,” he continued. “Then, it may be too late for them.”

Image Credits: Flickr – Metropolitan Transport Authority, Tel Aviv University.

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