Researchers from the University of Pittsburgh have reported concerning cases of urticaria (hives) in participants receiving experimental HIV-1 mRNA vaccines, according to findings published April 29 in the Annals of Internal Medicine. While the vaccines were generally well-tolerated, the persistent nature of the skin reaction in some participants raises new safety considerations for mRNA vaccine platforms beyond COVID-19 applications.
The phase 1 randomized trial, known as HVTN 302, enrolled 108 HIV-negative volunteers aged 18 to 55 years who were randomly assigned to receive one of three investigational HIV-1 trimer mRNA vaccines at either 100 or 250 microgram doses. The vaccine candidates included a gp140 soluble trimer, a gp151 membrane-bound trimer, and a gp151 CD4KO membrane-bound trimer.
Urticaria Emerges as Notable Adverse Event
While most adverse events were mild or moderate and expected, investigators identified an unusual pattern of urticaria among participants. Seven individuals (7% of the study population) reported urticaria that was determined to be related to the study vaccines. More concerning, four of these participants continued to experience unresolved, intermittent urticaria at the 12-month follow-up mark.
"The pattern of urticaria observed in this trial deserves special attention," said Dr. Sharon A. Riddler, the study's lead author. "While the overall safety profile was similar to what we've seen with COVID-19 mRNA vaccines, the persistence of urticaria in some participants was unexpected."
Potential Link to Prior mRNA Vaccine Exposure
A post-hoc analysis revealed a striking pattern: 100% of participants who developed urticaria had previously received the Moderna COVID-19 mRNA vaccine, compared to only 37% of those without urticaria. Conversely, only 29% of the urticaria group had received Pfizer-BioNTech vaccines, versus 76% of participants without urticaria. None of the affected participants reported having no prior mRNA vaccine exposure.
The researchers found no associations between urticaria and demographic characteristics, history of allergies, medication use, or COVID-19 infection. The specific mechanism behind this potential correlation remains unclear and will require further investigation.
Overall Safety Profile
Beyond the urticaria cases, the vaccines demonstrated a safety profile generally consistent with previous mRNA vaccines. Mild-to-moderate local and systemic reactions were common, similar to those observed with licensed COVID-19 mRNA vaccines.
In total, 80 participants reported 190 unsolicited adverse events, with 30 events considered related to the study vaccines. Of these related events, 73% were classified as mild, with the remainder being moderate in severity.
Implications for HIV Vaccine Development
This study represents an important step in applying mRNA technology to HIV vaccine development, a field that has faced numerous challenges over decades of research. The ability to rapidly design and produce mRNA vaccines encoding complex HIV envelope proteins offers new possibilities for addressing this persistent global health challenge.
"The HVTN 302 study vaccines were generally safe and tolerable," the authors noted in their publication. However, they emphasized that the urticaria findings warrant careful monitoring in future trials of mRNA-based HIV vaccines.
The results come at a critical time as researchers worldwide are working to apply mRNA technology—which proved remarkably successful for COVID-19 vaccines—to other infectious diseases including HIV, influenza, and malaria.
Future Research Directions
An accompanying editorial in the Annals of Internal Medicine suggests that future studies should include more detailed immunological assessments to better understand the mechanism behind the urticaria reactions, particularly their potential relationship to prior mRNA vaccine exposure.
The findings also highlight the importance of extended follow-up periods in early-phase vaccine trials, as some adverse events may persist long after vaccination.
As mRNA vaccine technology continues to expand beyond COVID-19 applications, these results provide valuable safety signals that may inform the design and monitoring of future clinical trials, particularly for complex pathogens like HIV where multiple vaccine doses may be required for efficacy.
