Human Vaccines & Immunotherapeutics: news

Promising candidates for SARS-Co-V-2 vaccine

More than 100 vaccines for SARS-CoV-2 are at various stages of development, according to Nature. One of the most advanced candidates is an adenovirus-vectored spike protein-targeting vaccine (CanSino), which is poised for starting a Phase 2 trial. The results of the Phase 1 trial, which enrolled >100 participants, remain unpublished.

The DNA vaccine INO-4800 (Inovio) has enrolled 40 healthy volunteers in a Phase 1 study, with results expected in summer 2020. INO-4800 is a plasmid vaccine delivered by intradermal injection followed by electroporation.

An inactivated vaccine PiCoVacc (Sinovac) was immunogenic and protective in rhesus macaques in a challenge study.¹ None of the vaccinated animals developed COVID-19 disease following virus challenge to the lungs.

Another vaccine, which might advance to clinical testing in 2020, is based on a recombinant DNA technology (Sanofi) targeting the spike protein from SARS-CoV-2, combined with the AS03 adjuvant (GSK), which has been used to formulate pandemic H1N1 influenza vaccine.

The new coronavirus that emerged in Wuhan, China at the end of 2019 has spread worldwide, causing millions of infections and hundreds of thousands of deaths.

New checkpoint inhibition immunotherapeutic improves survival of lung cancer patients

The PD-1 inhibitor cemiplimab (Libtayo, Sanofi & Regeneron) extended survival by 32% compared to platinum chemotherapy in PD-L1-positive subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC). The Phase 3 trial, which enrolled >700 patients, tested cemiplimab as a first-line monotherapy. The benefit is comparable to that of the marketed PD-1 inhibitor pembrolizumab.

There are >2 million annual cases of lung cancer globally. NSCLC accounts for 85%, of which ~25% test positive for the PD-L1 biomarker.

Phase 1 testing is completed for two MERS vaccines

A modified vaccinia Ankara vaccine vectoring MERS spike protein was safe and immunogenic in an open-label Phase 1 study.² 23 healthy volunteers received two different dosage levels in two injections four weeks apart. The vaccine was well tolerated with no serious adverse events and elicited both humoral and cellular immune responses.

Another spike glycoprotein-targeting candidate, the DNA vaccine INO-4700 (Inovio & GeneOne), was well tolerated and elicited both B- and T-cell responses in a Phase 1/2a trial. The vaccine was administered intradermally in two or three doses. All participants in the 3-dose groups reported seroconversion and the ability of sera to neutralize the virus in vitro.

Immunotherapy before surgery improves responses in HER2-negative breast cancer

The PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca), given prior to chemotherapy and surgery, induced pathological complete response in 37% of HER2-negative breast cancer patients, compared to 22% in subjects who received chemotherapy alone before surgery. Complete responses were observed in 47% vs. 27% in triple-negative and 28% vs. 14% in estrogen receptor-positive breast cancers. The experimental group suffered serious adverse events more frequently.Durvalumab targets the immune checkpoint PD-1 pathway, which is exploited by some tumors to inhibit immune responses. Durvalumab is approved for use in some types of lung and bladder cancers.

Checkpoint blockade with chemotherapy benefits bladder cancer patients

The PD-1 inhibitor pembrolizumab (Keytruda, Merck) administered after platinum chemotherapy improved survival and delayed progression in subjects with metastatic urothelial carcinoma.³ The randomized, placebo-controlled Phase 2 trial involved 108 patients and determined the progression-free survival to be 5.4 and 3.0 months for the experimental and placebo cohorts, respectively, with overall survival of 22 vs. 19 months.

“This trial, along with another recent study testing a similar approach, bolster the use of [immunotherapy following chemotherapy], which will likely become a standard of care for metastatic urothelial cancer, a disease characterized by a paucity of advances in decades,” lead author Matthew Galsky of Icahn School of Medicine at Mount Sinai said.

VLP vaccine in preclinical development might protect from multiple Ebola strains

A novel Ebola virus-like particle vaccine, which incorporates glycoproteins from the Zaire and Sudan strains, elicited strong humoral and antibody-mediated cell responses in rhesus macaques.⁴ Immunization of rabbits elicited antibodies that neutralized all four known pathogenic Ebola strains.The MVA- and VSV-vectored Ebola vaccines are in clinical trials and field use in an outbreak in several African countries. However, they might require a booster dose for durable and broad immunity.

Recombinant IL-12 enhances immunotherapy

Interleukin 12 (IL-12) increased intratumoral inflammation and improved checkpoint blockade immunotherapy in a mouse model of melanoma.⁵ The recombinant cytokine was fused to a collagen-binding domain, which targets the exposed collagen in the leaky vasculature in the tumor. The combination with a checkpoint inhibitor eradicated large tumors in the experimental animals.“These positive results are in tumors where checkpoint inhibitors normally don’t do anything at all. We expected this therapy to work well, but just how well it worked was surprising and encouraging,” senior author Jeffrey Hubbell of University of Chicago said.

New Plasmodium antigen identified from resistant hosts

A vaccine targeting a novel antigen partially protected non-human primates from malaria in a challenge study.⁶ When bound by an antibody, the P. falciparum glutamic-acid-rich protein (PfGARP) triggers programmed cell death in the parasite. The protein is expressed in the trophozoite stage of the life cycle.

Antibodies against PfGARP were identified by comparing blood of resistant and susceptible people. Tanzanian children without anti-PfGARP antibodies had a 2.5-fold higher risk of developing severe malaria, and the antibodies successfully killed infected erythrocytes in cell culture.