What’s New in Next-Generation Vaccines for Respiratory Viruses?

In a review published earlier this year, authors David M. Morens, MD; Jeffrey K. Taubenberger, PhD, MD; and Anthony S. Fauci, MD, of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, looked at possible approaches to new vaccines against viruses that replicate the human respiratory mucosa, focusing on the challenges that have thus far impeded successful development of mucosal respiratory vaccines. These viruses include influenza A, COVID-19, endemic coronaviruses, respiratory syncytial virus (RSV) and other “common cold” viruses, all which replicate quickly and rapidly transmit to other hosts, “within a narrow window of time before adaptive immune responses are fully marshaled,” emphasized the authors.

In conducting this review,¹ the authors took into account a number of variables such as vaccine antigen configuration; dose and adjuventation; route and timing of vaccination; boosters needed for vaccines; adjunctive therapies; and current public health policies in regard to vaccine administration.

That effective vaccines are needed for these pathogens is essential. These viruses kill as many as 5 million people globally each year, with COVID-19 alone having killed more than one million people in the United States.

Furthermore, influenza vaccines, the authors noted, have changed little since their inception in 1957 into United States vaccination programs, and as of yet have been unable to create immunity over new seasonal strains of the virus. While vaccines for influenza reduce the risk of death, hospitalization, and severe disease, their effectiveness against infection over the past 15 years has ranged between 14% and 60%, with the current vaccines requiring annual revaccination with new formulations.

For COVID-19 vaccines, the continued emergence of new strains means current vaccine protection is short-lived, requiring the long, complex process of new vaccine development. This process, of course, also includes current vaccine candidates for RSV, parainfluenzaviruses, endemic coronaviruses, and other “common cold” viruses. Authors also emphasized that these respiratory viruses have short incubation periods and rapid viral replication.

Because natural mucosal respiratory virus infections cannot offer long-term protective immunity against reinfection, the challenges for future vaccine development are multifactorial:

• Natural infections of mucosal respiratory viruses are not fully controlled by human immune systems, because we have evolved to tolerate them during short periods of mucosal viral replication
• Mucosal and systemic immunity only partially protects against infection, which means alternative host immune mechanisms must be explored
• Immune correlates of protection against mucosal respiratory viruses are only partially understood
• Vaccine-related questions of route administration, antigen configuration, adjuventation, and association with adjunctive therapy are essential for current research
• Vaccinated hosts and host risk groups are plentiful and heterogeneous (will a one-size-fits-all vaccine really be useful?)
• Public health considerations for next-generation respiratory vaccines must include shaping vaccine design, schedules, role of boosting frequency and duration of protection, side effects, and public acceptance.

The authors concluded several important points. Firstly, durably protective vaccines against these mucosal respiratory viruses with high mortality rates have so far eluded vaccine development efforts. The challenges in vaccine development are both plentiful and complex. Moving forward, clinicians need to better understand why multiple sequential mucosal infections with identical circulating respiratory viruses, spread out through many years of life, still do not elicit natural protective immunity.

“We must think outside the box to make next-generation vaccines that elicit immune protection against viruses that survive in human populations because of their ability to remain significantly outside of the full protective reach of human innate and adaptive immunity,” the authors stated.

Reference

1. Morens DM, Taubenberger JK, Fauci AS. Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses. Cell Host Microbe. 2023;31(1):146-157. doi:10.1016/j.chom.2022.11.016