Delayed Antibody Treatment May Improve Efficacy of mRNA Vaccines

Investigators led by Pablo Penaloza-MacMaster, PhD, associate professor of Microbiology-Immunology, have discovered that administering an antibody treatment four days after mRNA vaccination enhances immune responses and vaccine efficacy in mice, according to a recent study published in The Journal of Clinical Investigation.

The findings suggest a potential strategy to advance the development of mRNA vaccines for treating infectious diseases such as HIV, coronaviruses and cancer.

During the COVID-19 pandemic, mRNA vaccines proved highly effective in preventing severe infection and death caused by SARS-CoV-2, the virus responsible for COVID-19. These vaccines employ laboratory-engineered mRNA to produce viral proteins, which then activate the body’s adaptive immune response.

While effective in reducing severe SARS-CoV-2 infections, current mRNA vaccines have exhibited limitations with immune durability, often requiring multiple booster doses to increase efficacy. They are also unable to fully prevent breakthrough infections, underscoring the need for improved vaccine strategies, according to Penaloza-MacMaster.

In the current study, Penaloza-MacMaster and his team investigated whether reinforcing a costimulatory response known as 4-1BB by using costimulatory antibodies could enhance the effectiveness of mRNA vaccines.

“T-cells require at least two critical signals for activation, known as antigen and costimulation,” Penaloza-MacMaster said. “It’s like starting a car: the antigen is the key, which fits perfectly with your T-cell and turns the car on. But you also need to press the gas pedal, which is the costimulation.”

Administering both signals simultaneously, however, can be counterproductive, Penaloza-MacMaster said, as previous attempts to enhance T-cell responses by providing costimulatory antibodies at the time of vaccination have been unsuccessful.

This prompted the investigators to explore whether delaying the costimulatory treatment until days after the initial mRNA vaccination could better support T-cell activation and improve vaccine efficacy.

“It seems you need to turn on the key and let the car warm up before you press the gas pedal,” Penaloza-MacMaster said.

First, the investigators immunized mice with various mRNA vaccines and then administered a low dose of 4-1BB costimulatory antibodies at the time of vaccination or four days later. These antibodies, which promote T-cell activation, have previously been tested in treatments for autoimmune diseases and cancer immunotherapy and at low doses have shown to be safe.

The scientists found that administering a low dose of 4-1BB costimulatory antibodies at the time of vaccination did not significantly enhance the mice’s immune response. However, delaying this treatment by four days significantly improved CD8 T-cell responses and increased the durability of the immune responses across multiple mRNA vaccines, including those for SARS-CoV-2, HIV-1 and cancer.

“We observed an improvement in the efficacy of mRNA vaccines,” Penaloza-MacMaster said. “Weeks after vaccination, the mice were exposed to various pathogens, and those treated with the delayed costimulatory therapy at day four cleared the infections more effectively than mice that did not receive the treatment. This day 4 treatment also improved the efficacy of cancer vaccines.”

According to Penaloza-MacMaster, these findings highlight the importance of the timing of co-stimulation to improve mRNA vaccine efficacy and reduce the likelihood of breakthrough infections.

“These data also warrant a re-evaluation of a classical textbook model in immunology, which proposes that T-cells must receive antigen and costimulation at the same time. Although these two signals are indispensable for T-cell activation, our data suggest that a time interval between them can enhance T-cell responses after vaccination,” Penaloza-MacMaster said.

Sarah Sanchez, a student in the Driskill Graduate Program in Life Sciences (DGP), was lead author of the study.

Co-authors include Tanushree Dangi, PhD, a research associate at Northwestern University; Min Han Lew, PhD, a postdoctoral fellow in the Penaloza-MacMaster laboratory; Bakare Awakoaiye, a student in the Medical Scientist Training Program (MSTP); Nahid Irani, a student in the Science Immersion Program (SIP); and Slim Fourati, PhD, assistant professor of Medicine in the Division of Allergy and Immunology.

Penaloza-MacMaster is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

This research was supported by the National Institute on Drug Abuse (grant DP2DA051912), the Third Coast Centers for AIDS Research (CFAR), and the National Institute of Allergy and Infectious Diseases (grant 1R56AI187084).