Scientists Develop Universal Vaccine Platform Protecting Against Multiple Respiratory Pathogens

Scientists have created a nasal vaccine that protected mice against multiple respiratory pathogens including flu, COVID-19, SARS, and bacteria, marking a fundamentally different approach to disease prevention. The vaccine, given in four doses of nasal spray over four weeks, produced protection lasting up to six months after immunization.

The vaccine contains a cocktail of substances intended to stimulate several aspects of the immune system. When researchers gave the treatment to mice and then exposed them to pathogens, one month after immunization, three months after immunization, and in some cases up to six months after immunization, the mice were protected against SARS-CoV-2, the original SARS pathogen, and another coronavirus, as well as other pathogens. The vaccine induced the formation of tiny immune structures in the lungs, fortresses from which the mouse's body could continually fight infection.

The vaccine platform contains molecules that can bind to and activate receptors in the body that are part of the immune system's internal communication network. It also contains a harmless antigen called ovalbumin, a protein found in eggs. The effect of these two elements together is to activate both the innate and adaptive immune systems.

Traditional vaccines work by priming the immune system to respond quickly to specific pathogens and rely on the adaptive immune response. The innate immune system kicks into gear very quickly after exposure to an infectious agent, producing a rapid but less specific response. This wanes after a few days, once the adaptive immune system has had a chance to mount a response more tailored to the specific pathogen.

The T cells recruited as part of the adaptive immune response keep the innate immune response on life support, long after it would usually have waned. In 2023, researchers published a study that showed the BCG vaccine is able to confer protection against diseases other than TB because it can produce both innate and adaptive immune responses that last.

Researchers noticed during the pandemic that people who received the BCG vaccine against tuberculosis had extra protection against COVID-19. That meshed with decades of observations that the shot prevents a smattering of other diseases. While the vaccine itself has a mixed success rate, BCG revs up the innate immune system, which is not specific to a given pathogen, and provides broad, albeit low-level, protection against many different infections.

Separately, a multidisciplinary team from the Wyss Institute at Harvard University, Dana-Farber Cancer Institute, and collaborating institutions has explored a different approach using a DNA origami nanotechnology platform called DoriVac that functions as both a vaccine and an adjuvant. In their experiments, DoriVac vaccines targeted a peptide region (HR2) that is conserved within the spike proteins of several viruses, including SARS-CoV-2, HIV, and Ebola.

In mice, the SARS-CoV-2 HR2 version of the vaccine triggered strong immune activity, including antigen-specific antibody responses (humoral immunity) and T cell responses (cellular immunity). The researchers also evaluated the vaccine using an advanced preclinical system that models the human immune system. Using the Wyss Institute's microfluidic human Organ Chip technology, they created an in vitro model of the human lymph node. Within this system, the SARS-CoV-2 HR2 vaccine also produced strong antigen-specific immune responses in human cells.

In a direct comparison with SARS-CoV-2 mRNA vaccines delivered in lipid nanoparticles, a DoriVac vaccine carrying the same spike protein variant produced a similarly strong activation of the human immune system. However, the DNA origami vaccine proved to be more stable and easier to store and manufacture. The findings were published in Nature Biomedical Engineering.

The vaccine design relies on small self-assembling square nanostructures made of DNA. One side of the structure displays adjuvant molecules arranged at carefully optimized nanometer spacing. The opposite side presents selected antigens such as peptides or proteins derived from tumors or pathogens. In earlier work involving tumor-bearing mice, DoriVac vaccines produced stronger immune responses than versions that lacked the DNA origami structure.

In humans, there are different structures in the nose and the throat and the deeper lung. Whether or not this type of vaccination can induce similar structures in humans is something that needs to be tested. The next step to building on these results will be further testing. Humans and mice, although they have their similarities, are different in many ways that could scuttle efforts to bring this approach closer to application.

The COVID-19 pandemic pushed messenger RNA (mRNA) vaccines into the spotlight of global health. After completing clinical trials, the first COVID-19 mRNA vaccine was administered on 8 December 2020. Modeling studies later estimated that these vaccines prevented at least 14.4 million deaths from COVID-19 during their first year of use. Clinical trials are now underway for vaccines targeting influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and tuberculosis bacteria.

The immune protection generated by COVID-19 mRNA vaccines can differ widely among individuals, and the protection tends to decline over time. The challenge becomes even greater because the SARS-CoV-2 virus continually evolves, producing new variants that can partially evade immune defenses. As a result, COVID-19 vaccines often need periodic updates. Manufacturing these vaccines can be complex and expensive, and scientists have limited control over the number of mRNA molecules packaged inside the lipid nanoparticles used for delivery. These vaccines also require cold storage and may sometimes cause unintended off-target effects.