RESUMEN
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains one of the top three causes of death. Currently, the only licensed vaccine against TB is the bacillus Calmette-Guerin (BCG), which lacks efficacy in preventing and controlling pulmonary TB in adults. We aimed to evaluate a nasal TB vaccine formulation composed of the Mtb-specific vaccine antigen ESAT-6, an Mtb-associated protein that can trigger protective immune responses, and S100A4, a recently characterized novel mucosal adjuvant. Mice were intranasally given recombinant ESAT-6 in the presence or absence of S100A4 as an adjuvant. We have provided experimental evidence demonstrating that S100A4 admixed to ESAT-6 could induce Mtb-specific adaptive immune responses after intranasal immunization. S100A4 remarkably augmented the levels of anti-ESAT-6 IgG in serum and IgA in mucosal sites, including lung exudates, bronchoalveolar lavage fluid (BALF) and nasal lavage. Furthermore, in both lung and spleen tissues, S100A4 strongly promoted ESAT-6-specific expansion of CD4 T cells. Both CD4 and CD8 T cells from these tissues expressed increased levels of IFN-γ, TNF-α, and IL-17, cytokines critical for antimicrobial activity. Antigen-reencounter-induced T cell proliferative responses, a key vaccine performance indicator, were augmented in the spleen of S100A4-adjuvanted mice. Furthermore, CD8 T cells from the spleen and lung tissues of these mice expressed higher levels of granzyme B upon antigen re-stimulation. S100A4-adjuvanted immunization may predict good mucosal protection against TB.
Asunto(s)
Adyuvantes Inmunológicos , Administración Intranasal , Antígenos Bacterianos , Proteínas Bacterianas , Mycobacterium tuberculosis , Proteína de Unión al Calcio S100A4 , Vacunas contra la Tuberculosis , Animales , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Ratones , Mycobacterium tuberculosis/inmunología , Femenino , Proteína de Unión al Calcio S100A4/inmunología , Linfocitos T CD4-Positivos/inmunología , Tuberculosis/prevención & control , Tuberculosis/inmunología , Adyuvantes de Vacunas/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Pulmón/inmunología , Pulmón/microbiología , Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Citocinas/metabolismo , Ratones Endogámicos C57BL , Bazo/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Ratones Endogámicos BALB CRESUMEN
The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than 6 months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel label-free technique for measuring germinal center activity. Importantly, S100A4 did not induce olfactory bulb inflammation after nasal delivery, which is often a safety concern for nasal vaccination. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2.