Hildegund C.J. Ertl, M.D.

We developed vaccines expressing the SARS-CoV-2 spike or nucleocapsid protein. The vaccines are being tested for T and B cell responses in mice. They are being tested in a hamster challenge model.

Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors.

In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.

This NIH-funded research aimed to test adenoviral recombinants based on simian serotypes for induction of immune responses to gag/pol/rev/env of HIV-1 or SIV-1 in mouse and primate models. Results were promising and part of the vaccines, based on two adenoviral vector vaccines expressing the HIV-1 env protein, are currently being tested in a phase I trial sponsored by HVTN.

The laboratory developed an adenovirus-based vaccine against rabies virus that can provide rapid immunity following a single administration. A simian adenoviral vector termed adenovirus C68 (AdC68) was generated as a molecular clone to express the glycoprotein of rabies virus. In mice, this vector induced complete protection to rabies virus challenge after a single dose. This vaccine also achieves long-term protection in non-human primates after a single dose. A slightly modified version of this vaccine has been tested in collaboration with The University of Oxford. Results were promising and a phase 1b/II trial is being initiated.

In collaboration with Virion Therapeutics, the laboratory developed a therapeutic vaccine against chronic hepatitis B virus (HBV) infection (CHB). The vaccines target viral polymerase and core proteins. Vaccines are delivered by chimpanzee adenovirus vectors (AdC) of serotype 6 (AdC6) and 7 (AdC7) used in prime-only or prime-boost regimens. The HBV antigens are fused into an early T cell checkpoint inhibitor, i.e., herpes simplex virus (HSV) glycoprotein D (gD), which enhances and broadens vaccine induced CD8+ T cell responses. The vaccines were shown to induce potent CD8+ T cells in mice which can reduce HBV viral loads in a surrogate model of CHB. Clinical trials are planned and expected to commence towards the end of 2022.

Reducing the metabolic stress within a tumor microenvironment could be essential to improve the effectiveness of active cancer immunotherapy. Using a mouse model of melanoma, the laboratory showed that appropriately timed treatment with the PPAR agonist fenofibrate improves the ability of a T cell-inducing cancer vaccine to delay tumor progression. The drug reduces the use of glucose by tumor and tumor stroma cells and promotes the use of fatty acids for their metabolic needs. The increased availability of glucose within the tumor microenvironment in turn allows for its increased use by vaccine-induced tumor-infiltrating CD8+ T cells, which improves their ability to slow tumor progression. The laboratory is currently using a humanized mouse model to test if similar results can be obtained with human melanomas.