Switching arms improves effectiveness of two-dose vaccinations, study suggests

The laboratory study led by researchers at Oregon Health & Science University measured the antibody response in the blood of 947 people who received two-dose vaccinations against COVID-19 early in the pandemic. Participants included OHSU employees who agreed to enroll in research while getting vaccinated against the SARS-CoV-2 virus, and were randomized to get the second dose in either the same or the opposite arm as the first dose.

The study published as a preprint in The Journal of Clinical Investigation.

Historically, clinicians thought that arm choice didn't matter.

The new study tested serum samples collected at various times after vaccination. They found a substantial increase in the magnitude and breadth of the antibody response among people who had "contralateral" -- or a shot in each arm -- boosting compared with those who did not.

The improved response clearly materialized three weeks after the second booster and persisted beyond 13 months after boosting. Investigators found heightened immunity to the original SARS-CoV-2 strain, and an even stronger immune response to the omicron variant that emerged roughly a year after arm alternation.

Researchers aren't sure why this happens, but they speculate that giving a shot in each arm activates new immune responses in different lymph nodes in each arm.

"By switching arms, you basically have memory formation in two locations instead of one," said senior author Marcel Curlin, M.D., associate professor of medicine (infectious diseases) in the OHSU School of Medicine and medical director of OHSU Occupational Health.

Laboratory research yields eye-opening results

OHSU had the opportunity to examine the question as part of a series of laboratory studies using blood drawn from willing employees beginning early in the COVID-19 pandemic. That line of research has produced a series of published studies related to the durability, breadth and potency of immune response following vaccination and breakthrough infections.

After vaccines became available in late 2020, some participants wondered whether it made a difference if they alternated arms in the two-dose regimen.

"This question hasn't really been extensively studied, so we decided to check it out," Curlin said. "It turned out to be one of the more significant things we've found, and it's probably not limited to just COVID vaccines. We may be seeing an important immunologic function."

Among the people in the study who agreed to switch arms, researchers matched 54 pairs for age, gender and relevant time intervals between vaccination and exposure -- half getting the two doses in one arm and half in both.

Two weeks after the second dose, researchers didn't see much of a difference in immune response. After three weeks, however, researchers measured significantly greater numbers of antibodies capable of binding and neutralizing the SARS-CoV-2 virus in blood samples. The rates progressively increased over four weeks from 1.3-fold to as much as a 4-fold increase against the omicron variant of the virus.

"Any incremental improvement might save a lot of lives," Curlin said.

Further research needed

At this point, most people have long since been exposed to the SARS-CoV-2 virus multiple times either through vaccination, infection or both.

Although the new study focused on vaccination against COVID-19, researchers say they expect the improved immune response could be similar for other multidose vaccinations. They call for further research to determine whether contralateral vaccination improves immune response for other vaccines, and especially among children.

"Several prime-boost vaccine regimens are essential components of pediatric care, and immune responses may differ in children," they write.

Curlin said further study is needed and it is too soon to make clinical recommendations based on the results of this study. If and when a new virus emerges requiring a new two-dose vaccine, Curlin said he won't hesitate.

"I'm going to switch up my arms," he said.

In addition to Curlin, co-authors include Sedigheh Fazli, Archana Thomas, Abram Estrada, David Xthona Lee, Steven Kazmierczak, Ph.D., Mark Slifka, Ph.D., and Bill Messer, M.D., Ph.D., of OHSU; Hiro Ross, a former OHSU medical student now doing residency at the University of California, Los Angeles; and David Montefiori, Ph.D., of Duke University.

The study was supported by the M.J. Murdock Charitable Trust; the OHSU Foundation; and the National Institutes of Health award R01AI145835 and P51OD011092. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.