Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice

Abstract

As mRNA vaccines have proved to be very successful in battling the coronavirus disease 2019 (COVID-19) pandemic, this new modality has attracted widespread interest for the development of potent vaccines against other infectious diseases and cancer. Cervical cancer caused by persistent human papillomavirus (HPV) infection is a major cause of cancer-related deaths in women, and the development of safe and effective therapeutic strategies is urgently needed. In the present study, we compared the performance of three different mRNA vaccine modalities to target tumors associated with HPV-16 infection in mice. We generated lipid nanoparticle (LNP)–encapsulated self-amplifying mRNA as well as unmodified and nucleoside-modified non-replicating mRNA vaccines encoding a chimeric protein derived from the fusion of the HPV-16 E7 oncoprotein and the herpes simplex virus type 1 glycoprotein D (gDE7). We demonstrated that single low-dose immunizations with any of the three gDE7 mRNA vaccines induced activation of E7-specific CD8 + T cells, generated memory T cell responses capable of preventing tumor relapses, and eradicated subcutaneous tumors at different growth stages. In addition, the gDE7 mRNA-LNP vaccines induced potent tumor protection in two different orthotopic mouse tumor models after administration of a single vaccine dose. Last, comparative studies demonstrated that all three gDE7 mRNA-LNP vaccines proved to be superior to gDE7 DNA and gDE7 recombinant protein vaccines. Collectively, we demonstrated the immunogenicity and therapeutic efficacy of three different mRNA vaccines in extensive comparative experiments. Our data support further evaluation of these mRNA vaccines in clinical trials.

mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

“…Conversely, irrelevant mRNA lacking HPV antigen expression failed to induce the suppression of tumor growth, as demonstrated by other research studies. 19,41 Thus, mHTV is expected to exert therapeutic effects in the patients infected with HPV types 16 and 18 and show preventive effects against the progression of precancerous lesions. 42 Currently, DNA vaccines are the most widely used vaccines that have been proven to be effective in clinical trials (NCT01634503, and NCT00788164).…”

Messenger RNA Therapy for Female Reproductive Health

“…169 Additionally, vaccination with self-amplifying mRNA of three HPV antigens has shown efficacy in eradicating subcutaneous HPV+ tumors at various stages and preventing their relapse. 170 A previous study has shown that HPV vaccination for the treatment of cervical cancer using a traditional vaccine was most effective when combined with the chemotherapeutic agent cisplatin. 171 As such, future mRNA LNP vaccines may incorporate a combinatorial treatment strategy with traditional chemotherapeutics.…”

“…One study showed that such HPV vaccination activated antigen-specific effector cells to attack subcutaneous HPV+ tumors, and circulating memory CD8 + T cells protected from relapse . Additionally, vaccination with self-amplifying mRNA of three HPV antigens has shown efficacy in eradicating subcutaneous HPV+ tumors at various stages and preventing their relapse . A previous study has shown that HPV vaccination for the treatment of cervical cancer using a traditional vaccine was most effective when combined with the chemotherapeutic agent cisplatin .…”

Decoding immunogenic cell death from a dendritic cell perspective

“…100 While these DCs truly recapitulate features and functions of in vivo cDCs, the yield remains low, limiting their widespread use for vaccination purposes. With new technologies emerging to target cDCs in vivo using antibody-based strategies 7 or lipid nanoparticles (LNPs) as carriers to deliver tumor antigens to DCs, 101,102 in vivo targeting might become the preferred strategy for DC vaccination purposes. Broadly speaking, immunogenicity is determined by a combination of two properties: antigenicity and adjuvanticity.…”