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Like scores of other physicians and healthcare workers, T.J. Maltese, DO, a neurologist in private practice on Long Island in New York state, had no problem with his first dose of the Moderna coronavirus vaccine -- but he was knocked out by the second.

Maltese got his second shot at 4:30 p.m. on a Friday. Within 2 hours his arm was sore. He developed flu-like symptoms overnight, and had chills and body aches on Saturday. His low-grade fever (peaking at 101.4°F) lingered all day. If he had to work, he could have pushed through, he said, but he rode out his symptoms on his couch with the help of the occasional Tylenol.

By 9 p.m. Saturday, Maltese started to feel better. He got a good night's sleep and was back to normal on Sunday.

"I know plenty of people with minimal symptoms after the second dose, so it's not definite you'll feel side effects," . "But be prepared for the possibility."

The healthcare worker scuttlebutt is that the second dose of any COVID-19 vaccine packs a punch -- unless you've already had COVID, then the first dose can hit just as hard.

These perceptions are substantiated by immunology and by data from the vaccines' phase III trials, and some hospitals have even altered their healthcare worker scheduling in anticipation of second-dose side effects.

Priming the Immune System

Immunologists and infectious disease experts interviewed by MedPage Today said it's not unexpected that second-dose reactions are more intense than the first.

"The first time the immune system comes into contact with something, it's getting primed," said Purvi Parikh, MD, an immunologist at NYU Langone Health in New York City. "That goes for everything, from vaccines to allergies. It's rare on the first time to have a strong reaction. After that, the immune system recognizes it, so you have a much stronger reaction."

"We saw it in the trials, so it's really not surprising," Parikh added. "Now we're seeing it in real time as the vaccines are being rolled out."

In both and phase III trial data, systemic adverse events were reported more frequently after dose 2 than dose 1. For the latter, rates were 54.9% versus 42.2% for placebo after the first dose and 79.4% versus 36.5% for placebo after the second dose. Fever, headache, fatigue, myalgia, arthralgia, and chills were far more common after the second dose compared with the first dose and with all placebo doses.

Stanley Weiss, MD, an infectious disease specialist and epidemiologist at Rutgers New Jersey Medical School, said since his institution served as a site for the Moderna trial, the primary investigator was able to give faculty and administrators an early update on what to expect following vaccination.

"They said there was a very high rate of fatigue after the second dose, so we encouraged administrators ... to figure that many healthcare workers getting the vaccine might not be well enough to work the day after the second dose," Weiss told MedPage Today.

Weiss added that administrators were also careful not to vaccinate staff from within the same unit -- an ICU team, for instance -- on the same day.

Fewer Problems for Older Patients?

Both Weiss and Parikh said they had a far stronger response to the second dose of the Moderna and Pfizer vaccines, respectively. Weiss had fatigue and a severe headache for 2 days. Parikh's chills, fatigue, and headache resolved within 24 to 36 hours.

Zubin Damania, MD, a.k.a. , said the second dose of his Moderna vaccine knocked him out: "I couldn't sleep, I had a fever, rigors, body aches, a headache -- full-on man-flu," he joked on a .

His guest for that show was vaccine expert Paul Offit, MD, who also had fever and fatigue for about 48 hours after the second dose of the Pfizer vaccine.

"That reaction is less common in people over 65, and I'm over 65, so I'm thinking I'm not going to suffer that, but I did," Offit said.

Indeed, older patients are thought to have less of a reaction due to typical weakening of the immune system as people age, Parikh said: "The idea is that their immune system is not as robust as a young person's."

Dose 1 Rougher for Those with Previous COVID

Parikh said the same immunological concept behind a stronger response to the second dose also applies to first-dose effects for those who've had COVID-19 before.

"It's the same reason why some people who've had COVID and recovered get these effects with the first shot sometimes. The immune system has seen it before," she said.

Victoria Arthur, MD, of Lexington Pediatrics in Massachusetts, suspects she had COVID in March 2020, but wasn't able to confirm her diagnosis. Still, while all of the other physicians and healthcare staff in her office felt fine after the first dose of the Moderna vaccine, she did not.

"How I felt was how everyone else was describing their second vaccine," Arthur told MedPage Today.

Within three hours of her first dose, she had a headache, neck pain, and cognitive fog. She woke up at 3 a.m. with bad nausea and stomach cramps, and spent the entire next day in bed. By Monday, though, her only lingering symptom was a sore arm.

Her reaction to her second dose was similar, she said. Nonetheless, she was glad for it.

"I'm always grateful when I have a reaction, that means the body is doing its thing," she said. "I'm very fortunate to have been given the vaccine, so any side effect is worth it."

Being appreciative of having been vaccinated, despite the side effects, was a common sentiment among these healthcare professionals.

Weiss said second-dose side effects shouldn't deter anyone from getting vaccinated: "The benefits greatly overwhelm the risk of side effects. It's not a reason to delay."

"I'll take 30 hours of some mild misery," Maltese said, "over days to weeks of much worse -- and more unpredictable -- misery."

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