Vol.:(0123456789) 1 3 Cellular and Molecular Life Sciences (2021) 78:1191–1206 https://doi.org/10.1007/s00018-020-03652-2 REVIEW Twenty years of research on HPV vaccines based on genetically modifed lactic acid bacteria: an overview on the gut‑vagina axis Sedigheh Taghinezhad‑S 1  · Hossein Keyvani 2  · Luis G. Bermúdez‑Humarán 3  · Gilbert G. G. Donders 4,5  · Xiangsheng Fu 6  · Amir Hossein Mohseni 1 Received: 23 February 2020 / Revised: 3 September 2020 / Accepted: 16 September 2020 / Published online: 26 September 2020 © Springer Nature Switzerland AG 2020 Abstract Most cervical cancer (CxCa) are related to persistent infection with high-risk human papillomavirus (HR-HPV) in the cervical mucosa, suggesting that an induction of mucosal cell-mediated immunity against HR-HPV oncoproteins can be a promising strategy to fght HPV-associated CxCa. From this perspective, many pre-clinical and clinical trials have proved the potential of lactic acid bacteria (LAB) genetically modifed to deliver recombinant antigens to induce mucosal, humoral and cellular immunity in the host. Altogether, the outcomes of these studies suggest that there are several key factors to consider that may ofer guidance on improvement protein yield and improving immune response. Overall, these fndings showed that oral LAB-based mucosal HPV vaccines expressing inducible surface-anchored antigens display a higher potential to induce particularly specifc systemic and mucosal cytotoxic cellular immune responses. In this review, we describe all LAB-based HPV vaccine investigations by reviewing databases from international studies between 2000 and 2020. Our aim is to promote the therapeutic HPV vaccines knowledge and to complete the gaps in this feld to empower scientists worldwide to make proper decisions regarding the best strategies for the development of therapeutic HPV vaccines. Keywords Human papillomavirus · Lactic acid bacteria · Lactococcus lactis · Lactobacillus casei · Vaccine · Cervical cancer Introduction Cervical cancer (CxCa) is considered the 4th most com- mon cancer in women after breast, colorectal and lung [1]. Development of CxCa is closely associated with persistent genital infection with high risk human papillomavirus (HR-HPV) [2]. According to previous publications, HPV type 16 (HPV-16) is considered as the main widespread genotype associated with development of invasive CxCa [3, 4]. High prevalence of HPV infection, genital warts, and CxCa has encouraged researchers to pursue experimental lines of investigation for the development and widespread delivery of safe and efective prophylactic HPV vaccines to control HPV infection [5]. Most prophylactic vaccines to prevent HPV infections are based on virus-like particle (VLP) derived from HPV L1 capsid proteins. Although HPV vaccines are now used worldwide to block HPV infection, they are not efcient to treat (i.e., a therapeutic efect) per- sistent infections in millions of patients, who have already been infected with HPV [6, 7]. Thus, scientifc communities focus on developing therapeutic HPV vaccines which can stimulate robust immunogenicity against HPV oncoproteins. Indeed, it has been demonstrated that high-risk E6 and E7 oncoproteins are constitutively expressed in CxCa and thus they represent reliable candidates for the development of therapeutic vaccines against HPV-associated CxCa [8]. So Cellular and Molecular Life Sciences * Amir Hossein Mohseni amho.mohseni@gmail.com 1 Department of Microbiology, Faculty of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran 2 Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran 3 Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France 4 Department of Obstetrics and Gynaecology, Antwerp University Hospital, Antwerp, Belgium 5 Femicare Clinical Research for Women, Tienen, Belgium 6 Department of Gastroenterology, The Afliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China