What are the present challenges and future considerations in developing vaccines against mucosal respiratory viruses?

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In a recent review published in Cell Host & Microbe, the former director of the National Institute of Allergy and Infectious Diseases and former chief medical advisor to the president of the United States (U.S.), Dr. Fauci, and his team reviewed the roadblocks to developing effective vaccines against viruses that infect the human respiratory mucosa. The team also discussed strategies for next-generation vaccine development against mucosal respiratory viruses.

Study: Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses. Image Credit: Treecha/Shutterstock
Study: Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses. Image Credit: Treecha/Shutterstock


The recent coronavirus disease 2019 (COVID-19) pandemic has emphasized the severity and mortality rates associated with respiratory viruses. The influenza virus is thought to cause 12,000 to 52,000 deaths in the U.S. annually, while parainfluenzaviruses and respiratory syncytial virus (RSV) add to the mortality rates. The COVID-19 etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to have caused over a million deaths in the U.S.

The success of vaccines against some major respiratory viruses, such as mumps, measles, and rubella, fueled the hope of developing vaccines against all respiratory viruses. However, the quest to develop a universal influenza vaccine has been unsuccessful. This lack of success in vaccine development is linked to how vaccine-controlled viruses differ in infection progression from other respiratory viruses.

Viruses such as mumps, measles, and rubella cause widespread viremia throughout the body after the initial mucosal replication, which brings the virus in contact with various immune compartments and cell types. Coupled with their long incubation period, this results in the induction of strong, long-term, adaptive immunity. In contrast, other respiratory viruses such as SARS-CoV-2, RSV, and influenza do not cause widespread systemic infections and have short incubation periods, which do not elicit strong or long-lived adaptive immune responses. Additionally, these viruses also exhibit high tolerance to mutations, resulting in the rapid emergence of variants with changed antigenicity.

Major findings

The review reported that the complex tolerance regulation expressed by the respiratory immune system in humans, combined with the short incubation period of non-systemic respiratory viruses, could explain the lack of durable immune responses against these viruses. Additionally, the respiratory immune system comprises separate, tissue-specific regions, including mucosal-associated lymphoid tissues (MALTs), nasopharyngeal-associated lymphoid tissue (NALT), tear/conjunctival-associated lymphoid tissue (TALT), and bronchial-associated lymphoid tissue (BALT), each of which independently senses the virus, presents antigens, elicits local effector responses, and maintains tolerized immune states.

Non-systemic respiratory viruses have evolved to the tolerized immune environments in humans, and developed methods to replicate and spread before adaptive immune responses are generated to control the infection. These methods include, among others, the inhibition of host interferon responses and the presentation of decoy antigens.

Studies in human and animal models have shown that non-systemic mucosal respiratory viruses can be controlled more effectively with secretory mucosal immunity than systemic immunity. Memory T cells residing in tissues respond faster to mucosal infection through secretory immunoglobulin A (sIgA) expressed by plasma cells and effector and memory T cells present in the MALT.

Next-generation vaccines

To develop effective next-generation vaccines, it is essential to understand the immunological correlates of protection. In the case of influenza, the T cell and mucosal immunological correlates observed during influenza infections were not observed in influenza challenge studies among individuals vaccinated with inactivated or live-attenuated influenza vaccines. Recent studies have also reported that compared to correlates such as stem antibody titers and hemagglutinin head, serum neuraminidase antibody levels were a more accurate measure of protection. Despite this finding, neuraminidase has not been well-explored as a vaccine target.

The authors also believe that a consensus on the level of protection desired against non-systemic mucosal viruses is important for developing vaccines. The aims could include the complete prevention of the infection, as in the case of systemic respiratory viruses, limiting the replication and transmission of the viruses, preventing disease, or preventing only the severe outcomes of infection, such as hospitalization or death, as was the case for most COVID-19 vaccines.

The widespread presence of mucosal surfaces in the human body and the predominance of sIgA in these surfaces indicates that mucosal immunization is a promising avenue for developing vaccines against non-systemic mucosal viruses. However, aspects such as formulations, dosage, frequency of administration, and surmounting the immune tolerance challenges also need to be considered.

Given the fact that the vaccines that were successful in eliciting long-lasting protective immunity against systemic respiratory viruses were systemically replicating live viruses, live virus vaccines need to be considered as potential options despite the safety and development constraints. Additionally, the ability of the vaccine antigens to induce broadly protective immune responses against distantly related viruses also needs to be addressed during vaccine development.

Public health policies regarding next-generation vaccines against non-systemic mucosal viruses such as influenza and SARS-CoV-2 need to focus on decisions about dosages and frequencies of vaccines, as well as mixed-sequential vaccines where the primary and booster vaccines differ. Studies with RSV indicate repeated antigenic exposures might be more important in granting protection than immune memory.


Overall, the review comprehensively addressed the challenges in developing durable protective immunity against mucosal respiratory viruses that do not cause systemic infection. The authors also discussed potential directions and goals for next-generation vaccine development and the public health policies that must be considered while designing vaccination strategies.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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