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Latest Wistar Discoveries: Fine-tuning Vaccine Delivery in Preclinical Models to Advance MERS DNA Vaccine Candidate and Discovering New Targets for Cancer Therapy

April 27, 2021

A team of Wistar scientists led by Dr. David Weiner, Wistar executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research, and Dr. Ami Patel, Caspar Wistar Fellow, and collaborators have developed a synthetic DNA vaccine candidate for Middle East respiratory syndrome coronavirus (MERS-CoV).

A vaccine candidate based on their research was shown to be safe and tolerable in a recently completed human phase 1 study with a three-dose intramuscular injection regimen and is currently in phase 1/2a trial.

Our scientists continue to expand the preclinical studies of the vaccine in support of its clinical development. They have now tested intradermal delivery using a shortened two-dose immunization schedule in non-human primates (NHP).

“Low-dose delivery and shortened regimes are crucial to rapidly induce protective immunity, particularly during emerging outbreaks, as the current SARS-CoV-2 pandemic has emphasized,” said Weiner.

In a paper published in the journal JCI Insight, he and colleagues reported that low-dose intradermal administration induces potent immunity and protects from virus challenge. The low-dose regimen with intradermal delivery was more impactful in controlling disease and symptoms than the higher dose given intramuscularly.

“Intradermal delivery of synthetic DNA vaccines has significant advantages for rapid clinical development. It can be dose sparing and has higher tolerability in people compared with intramuscular injection,” said Patel.

Their experience developing this MERS vaccine candidate helped the team advance a COVID-19 vaccine through clinical trials in a short time.

Vaccine candidates that are simple to deliver, well tolerated, and can be readily deployed in resource-limited settings will be important to achieve control of infection for coronaviruses and other emerging infectious diseases.

The lab of Dr. Rugang Zhang, deputy director of The Wistar Institute Cancer Center, Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program, studies the process of cellular senescence and the changes in gene expression that accompany it.

Cellular senescence is a stable state of growth arrest in which cells stop dividing but remain viable and produce an array of inflammatory molecules collectively defined as senescence-associated secretory phenotype (SASP). These molecules account for the complex crosstalk between senescent cells and neighboring cells and the effect of cellular senescence in various physiological processes like aging and diseases like cancer.

Although senescence is regarded as a powerful barrier for tumor development, the SASP plays a role during tumor development promoting the growth of established tumors.

In a new study published in Nature Cell Biology, Zhang and colleagues pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules.

“This mechanism may potentially be targeted to stop the tumor-promoting aspect of senescence while preserving its antitumor function,” said Zhang.

The team focused on two proteins called METTL3 and METTL14 that are known for other molecular functions and found that these proteins moonlight as regulators of gene expression that help turn on SASP genes.

“Although we focused on senescence, we envision that this function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study,” said Zhang.