Humoral response induced after intranasal vaccination with heat inactivated Acinetobacter baumannii protects immunodeficient mice against hypervirulent LAC-4 strain

Thomas Rouma¹Emeline Barbieux¹Lorenzo Bossi²Sébastien Denanglaire²Yohannes Tafesse²David Vermijlen²Sandrine Delbauve²Véronique Flamand²Juliette Marguerite³Charles Van Der Henst³Xavier De Bolle¹Fabienne Andris²Eric Muraille^4,5*

• ¹Universite de Namur Unite de recherche en biologie moleculaire, Namur, Belgium
• ²ULB Center for Research in Immunology, Gosselies, Belgium
• ³Microbial Resistance and Drug Discovery, Flanders Institute for Biotechnology (VIB), Brussels, Belgium
• ⁴Faculty of Medicine, Université libre de Bruxelles, Brussels, Belgium
• ⁵Fonds de la Recherche Scientific (FNS-FNRS), Bruxelles, Belgium

Acinetobacter baumannii is an opportunistic bacterium that causes serious nosocomial infections, including pneumonia and bacteremia, especially in immunocompromised individuals. Here, we first tested the ability of a vaccination protocol with the heat-killed (HK) A. baumannii strain LAC-4 to protect various models of immunodeficient C57BL/6 mice against pulmonary infection by LAC-4. We observed that mice deficient in Th1 (IL-12p35-/-, IFN--/-), Th17 (IL-17RA-/-) and T cells (-TCR-/-, TAP1-/-, CD3-/-) display higher susceptibility to LAC-4 infection, but that our protocol improves their resistance. In contrast, vaccinated B cell-deficient (MuMT-/-) mice appear unable to control the infection, demonstrating that humoral immunity is essential to vaccine protection. Vaccination of wild-type mice with an HK itrA strain deficient for capsule production failed to induce protection, showing that protective antibodies are mainly directed against the capsule. Our vaccination protocol also confers increased protection in wild-type mice vaccinated and then treated with cyclophosphamide; an immunosuppressive drug described to strongly increase the susceptibility of mice to A. baumannii infection. Finally, we demonstrate that HK LAC-4 can induce the activation of human monocyte-derived dendritic cells and T lymphocytes from peripheral blood mononuclear cells of healthy donors, suggesting that it may activate the human adaptive immune system and induce a protective memory response against A. baumannii. Overall, our results demonstrate that administration of HK bacteria can induce protective immunity against A. baumannii in both immuno-competent and immuno-compromised mice and that these HK bacteria can activate the human adaptive immune system.