A recombinant herpes virus expressing influenza hemagglutinin confers protection and induces antibody-dependent cellular cytotoxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-08, Vol.118 (34), p.1-10
• Main Authors: Kaugars, Katherine, Dardick, Joseph, de Oliveira, Anna Paula, Weiss, Kayla A., Lukose, Regy, Kim, John, Leung, Lawrence, Rajagopalan, Saranathan, Wolin, Sydney, Akabas, Leor, Knipe, David M., Bajic, Goran, Jacobs, William R.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Viral - blood; Antibodies, Viral - immunology; Antibody response; Antibody-Dependent Cell Cytotoxicity - immunology; Biological Sciences; Cytotoxicity; Effector cells; Female; Glycoprotein D; Glycoproteins; Hemagglutination; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinins; Herpes simplex; Herpes Simplex - immunology; Herpes Simplex - prevention & control; Herpes viruses; Herpesvirus 1, Human - physiology; Herpesvirus 2, Human - physiology; Homology; Immune system; Immunization; Immunization (passive); Infectious diseases; Influenza; Influenza A; Influenza Vaccines - administration & dosage; Influenza Vaccines - immunology; Interferon; Male; Mice; Mice, Inbred C57BL; Morbidity; Orthomyxoviridae - immunology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - prevention & control; Public health; Receptors; Toxicity; Vaccination; Vaccines; Viruses; α-Interferon; γ-Interferon
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2110714118

Despite widespread yearly vaccination, influenza leads to significant morbidity and mortality across the globe. To make a more broadly protective influenza vaccine, it may be necessary to elicit antibodies that can activate effector functions in immune cells, such as antibody-dependent cellular cytotoxicity (ADCC). There is growing evidence supporting the necessity for ADCC in protection against influenza and herpes simplex virus (HSV), among other infectious diseases. An HSV-2 strain lacking the essential glycoprotein D (gD), was used to create ΔgD-2, which is a highly protective vaccine against lethal HSV-1 and HSV-2 infection in mice. It also elicits high levels of IgG2c antibodies that bind FcγRIV, a receptor that activates ADCC. To make an ADCC-eliciting influenza vaccine, we cloned the hemagglutinin (HA) gene from an H1N1 influenza A strain into the ΔgD-2 HSV vector. Vaccination with ΔgD-2::HAPR8 was protective against homologous influenza challenge and elicited an antibody response against HA that inhibits hemagglutination (HAI⁺), is predominantly IgG2c, strongly activates FcγRIV, and protects against influenza challenge following passive immunization of naïve mice. Prior exposure of mice to HSV-1, HSV-2, or a replication-defective HSV-2 vaccine (dl5-29) does not reduce protection against influenza by ΔgD-2::HAPR8. This vaccine also continues to elicit protection against both HSV-1 and HSV-2, including high levels of IgG2c antibodies against HSV-2. Mice lacking the interferon-α/β receptor and mice lacking the interferon-γ receptor were also protected against influenza challenge by ΔgD-2::HAPR8. Our results suggest that ΔgD-2 can be used as a vaccine vector against other pathogens, while also eliciting protective anti-HSV immunity.