Introduction
The nasal mucosa constitutes the main site of entry of respiratory viruses. Although the immune response following infection by various viruses has been extensively studied, the early stages of infection at the mucosal entry site remain poorly explored.
Several studies have been conducted with both RSV (respiratory syncytial virus), SARS-CoV-2 and influenza (flu) virus in nasal turbinates and human lung tissues to investigate viral susceptibility and early patterns of local mucosal immune response.
In general, viruses actively infect nasal turbinate tissues, predominantly targeting airway cells, with a rapid increase in tissue-associated viral growth. Importantly, respiratory virus infection triggers strong innate antiviral and inflammatory immune responses in the nasal mucosa itself.
Many studies have shown that the activation of defense cells at the local level (nasal mucosa and upper airway) following viral infection may be even more extensive than that caused by virus infection at the pulmonary level.
These findings reveal differential tissue-specific innate immune responses in the upper respiratory tract as compared to the lower respiratory tract, which are different even depending on which virus is infecting individuals at the time of infection. Several studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions.
Thus, there is a need to better understand and address the stages of upper respiratory tract respiratory virus infection and the resulting immune responses within the multifactorial complexity of human lung and nasal tissues.
The innate immune system is present in the mucosa of the entire gastrointestinal tract. It is highly developed and specialized and is called mucosa-associated lymphoid tissue (MALT). At the level of the oral mucosa, lymphoid centers are found in the tonsils, at the border between the hard and soft palate, at the gingival and lingual level and in the parotid gland.
Tonsils are secondary lymphoid tissue located at the entry site of the upper respiratory tract, draining the nasal and oral cavity and are also an important reservoir of B and T cells. They are compartmentalized organs where follicles and germinal centers develop in response to antigens such as intranasal vaccines.
Intraepithelial T-type lymphocytes, mostly of the CD8+ type, are found in the mucosa, which unlike most other lymphocyte populations show limited antigen receptor diversity. In addition to scattered lymphocytes, the mucosal immune system contains organized lymphoid tissues from the Peyer's patches of the small intestine and the lymphoid follicles of the spleen.
The major antibody found in salivary fluid is secretory immunoglobulin A (IgA-s). Of the two subclasses of IgA, IgA1 and IgA2, the latter is predominant in saliva.
IgA-s is accompanied by IgG-s and IgM-s which inhibit the adherence of microorganisms at mucosal level and neutralize viruses. Saliva also contains the metalloproteinase system which is bactericidal in the presence of H2O2.
The immune response to oral antigens is different from responses at other sites because of the high concentrations of IgA-s antibodies and because of the tendency for protein antigens to induce tolerance rather than activation of T lymphocytes.
Mucosal antibodies are vital to protect the upper airway at the site of viral entry, just as serum antibodies protect the lower airway.
History of nasal vaccinations
The nasal route is particularly attractive because of its ease of administration and induction of potent immune responses, particularly in the upper respiratory tract. The nasal route for vaccination offers some important opportunities, especially for the prevention of respiratory disease. The immune response following intranasal administration can provide protection at the site of administration and at several effector sites as part of the common mucosal immune system.
The advantage of mucosal vaccination in viral and bacterial infections in different age groups could have enormous clinical relevance.
Intranasal administration of vaccines by means of a nasal spray applied to the nostrils is an attractive mode of immunization. The nose, similar to the mouth, is a practical site for vaccine delivery and nasopharynx-associated lymphoid tissue efficiently induces antigen-specific immune responses in mucosal and systemic immune compartments.
The development of nasal vaccines has proved challenging, but considerable progress has been made in the last decade. However, it is not yet entirely clear whether the response following intranasal vaccination is initiated in structured lymphoid tissue (nasal-associated lymphoid tissue (NALT)) or through the diffuse nasal mucosal structure.
Nasal spray influenza (flu) vaccines (live attenuated influenza vaccine [LAIV]) are available. Attenuated influenza vaccines (LAIV) generate both a cellular (defense cells) and humoral (antibodies) immune response that provides protection at the site of viral entry against subsequent infection.
The induction of antibodies in the mucosa itself by this type of nasal vaccines (LAIV) are the most important effect and could be a superior indicator of the local defenses generated.
This type of vaccine is licensed in the United States, Canada and part of Europe. Some advantages of these vaccines are that they simulate the natural route of infection and induce robust and long-lasting cellular and humoral immune responses that mimic the natural infection caused by the influenza virus.
The example of intranasal attenuated influenza (flu) vaccines
Attenuated influenza vaccines (LAIV) generate both a cellular and humoral immune response: mucosal IgA antibodies provide protection at the site of viral entry against subsequent infection.
The induction of mucosal antibodies by LAIV are the most important effect and could be a superior indicator of LAIV immunogenicity compared to serum antibodies.
Inactivated influenza vaccines (IIVs) are used worldwide and LAIVs are licensed only in the United States, Canada, Europe, Russia, and India. The IIVs currently in use induce a specific antibody response against the strain included in the vaccine that lasts up to 6 months post-vaccination, but generally do not provide broadly protective antibodies or memory B cells.
In contrast, attenuated vaccines generate persistent antibody responses, as well as memory B cells and CD4+ and CD8+ T cell-mediated responses for up to 1 year in children, although in adults it would be less effective (the immunological mechanisms that explain this difference are not fully understood).
Follicular T helper cells (FTH) play a critical role in the formation of germinal centers, as well as in the development of antibodies and a high-affinity B-cell immune response, thus vaccines that promote and maintain TFH are the most likely to generate durable antibody responses.
In the work of Sarah Lartey et al (citation 4) at an ENT center in the USA, 34 children and 31 adults were vaccinated at different times before scheduled tonsillectomy for chronic tonsillitis or tonsillar hypertrophy (2 to 5 days before, 6 to 9 and 10 to 22 days) with trivalent LAIV and compared with 6 healthy controls who were not vaccinated. Tonsil and serum samples were obtained on the day of tonsillectomy.
LAIV vaccine rapidly activated lymphoid follicles and follicular T Helper cells in children at 7-14 days post vaccination and to a lesser extent in adults. In addition, a long-term antibody response (up to 1 year) against all three viral strains was observed in children, whereas only specific antibodies against FLU B were observed in adults. The magnitude of tonsillar THF responses correlated inversely proportional to pre-existing IgA-type antibodies.
However, there is evidence suggesting a reduced effectiveness of intranasal attenuated quadrivalent vaccine in adults compared to IIV and these could be some of the reasons:
(1) Pre-existing immunity that suppresses mucosal replication of LAIV, which is a requirement for the induction of a protective immune response.
(2) Reduced viral infection by the H1N1 component of LAIV due to less binding to salicylic acid, unlike the H3N2 and B components.
(3) Acquisition of mutations in the M segment that affect vaccine stability (greater impact for the H1N1 component).
In summary, while there is evidence of lower efficacy of LAIVs over IIVs, LAIVs have some advantages such as route of administration that simulate the natural route of infection and induce robust and longer-lasting cellular and humoral immune responses that mimic natural influenza virus infection.
Authors: Scientific Advisory. Medical area. Science Team.
