Results from a Phase I clinical trial show early evidence of an intranasal vaccine providing broad immunity against multiple strains of the avian influenza virus, demonstrating promise as a preventive strategy for pandemic preparedness. The study, published today in Nature Communications, also proposes novel biomarkers of successful immunization with intranasal vaccines, whose absence has long hindered the development of this type of vaccine.
“The spread of H5N1 influenza in animals with spillover into human populations globally highlights the critical need for effective countermeasures to protect our communities from this and other pathogens with pandemic potential,” said senior author Justin Ortiz, MD, MS, professor of medicine at the University of Maryland School of Medicine (UMSOM) and vaccine researcher at the university’s Center for Vaccine Development and Global Health (CVD). “This trial shows that this intranasal, shelf-stable H5N1 vaccine could play a major role in pandemic preparedness, offering a practical and scalable way to help protect people from evolving strains of the virus.”
Current influenza vaccines are administered intramuscularly, resulting in a systemic immune response against a single strain that can effectively prevent symptoms from developing but doesn’t necessarily stop the virus from spreading. In contrast, intranasal vaccines can generate immunity in the mucosal tissues where the virus makes an entry, showing potential to prevent the spread of the infection.
The Phase I study evaluated the safety and early efficacy signs of a recombinant H5N1 influenza vaccine formulated with a nanoemulsion adjuvant designed to boost the immune response. A total of 40 healthy volunteers were recruited and randomized to receive one of three doses of the intranasal vaccine, a placebo, or a high dose of the vaccine without adjuvants. The intranasal vaccine was administered in two doses 28 days apart, followed by a boost with an inactivated intramuscular vaccine six months later.
The vaccine was shown to be safe and well tolerated, with the most common adverse effects reported being mild nasal symptoms within an hour of vaccination. After the final boost, volunteers who received the adjuvanted vaccine showed a strong immune response involving the production of antibodies and memory cells even at low antigen doses.
“The vaccine also helped the immune system recognize multiple versions of the H5N1 virus, which is key because there are different versions of the virus and they change over time,” said co-lead author Meagan E. Deming, MD, PhD, assistant professor of Medicine at UMSOM. “The use of the adjuvant also suggests this approach might allow for lower doses of the vaccine, which could make our current vaccine stocks available to more people in the event of an outbreak.”
Conventional influenza vaccines are typically evaluated using a hemagglutination inhibition assay, which measures the amount of neutralizing antibodies found in the serum of immunized patients. However, intranasal vaccines do not typically pass this test as they primarily prime the immune response in the mucosa without necessarily being detectable in the bloodstream—a major obstacle that has led to the failure of previous clinical trials for intranasal vaccines.
In the absence of established biomarkers of immune protection, Ortiz and colleagues ran extensive tests evaluating different levels of the immune response triggered by the intranasal vaccine. In addition, the final boost with an intramuscular vaccine allowed them to study the ability of the intranasal vaccine to prime the immune system and mount a stronger immune response six months later in the presence of the inactivated virus.
Based on their findings, the researchers propose using antibody-dependent cellular cytotoxicity (ADCC) and surface plasmon resonance (SPR) assays to evaluate the efficacy of intranasal vaccines in future clinical trials, together with measuring antibody levels in mucosal tissues rather than in the bloodstream. While the introduction of these methods in clinical trial evaluations could accelerate the development of intranasal vaccines, their performance will first have to be confirmed in larger studies.
This study underscored the promise of intranasal vaccines as part of next-generation influenza prevention strategies, according to co-lead author Franklin R. Toapanta, MD, PhD, associate professor of medicine at UMSOM. A key advantage of intranasal vaccines over intramuscular delivery is that they can confer protection against a broader range of strains. The study tested the efficacy of the vaccine against a total of six influenza strains, including a strain that is currently circulating and has been reported to cause infections in poultry, livestock and 70 human cases the U.S. since last year.
Mark T. Gladwin, MD, dean of the UMSOM and vice president for medical affairs at the University of Maryland, stated: “The research aligns with global public health priorities to develop vaccines that reduce transmission and provide broader protection against emerging influenza strains.”
