Author: The Wistar Institute

On March 12, the Pennsylvania Department of Labor & Industry (L&I) announced more than $6.5 million in PAsmart Registered Apprenticeship Grants. Wistar is one of the awarded institutions, receiving a $212,499 grant in support of the Expansion, Curriculum Evolution and Enhancement During Biomedical Technician Training (ExCEED BTT) program.

Building on the signature Biomedical Technician Training (BTT) Program, ExCEED BTT was designed to enhance training and expand opportunities for community college students to participate in paid pre-apprenticeship experiences that will prepare them for careers in the region’s growing biotechnology and biopharmaceutical sector.

PAsmart was launched in 2018 to increase STEM and computer science education following the “earn while you learn” model, in which trainees learn the skills that growing businesses need while working and earning a wage.

“We are extremely grateful to the PA Department of L&I for their continued support of Wistar’s efforts in training the next generation of life sciences professionals,” said Brian Keith, Ph.D., dean of biomedical studies at Wistar. “This award will allow us to augment our ongoing training mission and prepare our students for careers in the growing biomedical research workforce.”

In 2019, Wistar was one of the first institutions to receive funding from the PAsmart program after its launch.

Human papillomavirus (HPV) is the most commonly sexually transmitted virus in the world, infecting 75% of sexually active adults in their lifetime¹.

HPV infection has a dramatic impact on global health, with more than 500,000 cervical cancer cases diagnosed worldwide each year, the vast majority of which (around 85%) occur in the less developed regions² where no screening programs are available, and women are diagnosed at late stages. Globally, cervical cancer causes more than 260,000 deaths each year².

HPV also causes genital warts and other malignancies such as head and neck cancer, and men get HPV-related throat cancer as often as women get HPV-related cervical cancer. 

Making the HPV Vaccine: Challenges and Persistence

During a recent Wistar event, thought leaders in the field of HPV vaccines, Dr. Kathrin Jansen, Pfizer senior vice president and head of Vaccine Research and Development, and Dr. Iona Munjal, Pfizer director of Clinical Research and Development, laid the historical groundwork in their roles to develop, design and roll out the world’s first HPV vaccine.  

“This is the story of great scientific discovery, grit and persistence, and the breaking of dogmas,” said microbiologist and vaccinologist Dr. Jansen.

HPV was identified as the root cause of cervical cancer in the 1990s by German virologist professor Harald zur Hausen, who went on to win a 2008 Nobel Prize in Physiology or Medicine for revolutionizing cervical cancer research by discovering HPV DNA in cervical cancer biopsies. A seminal study in 1999 confirmed that HPV is a necessary cause of cervical cancer, as virtually all cervical lesions (99.7%) contain HPV DNA³.

According to Jansen, the early phases of vaccine development were surrounded by skepticism and it took much perseverance to overcome the technical challenges. In the process, she and the other scientists working in the HPV field broke some scientific dogmas, showing for example that, contrary to the common assumption that cancer development by HPV takes decades, it occurs relatively quickly (within 1-5 years from infection), which allowed for testing the vaccine effectiveness in a reasonable timeframe.

In several clinical studies the vaccines currently available showed excellent safety profiles and a remarkably high efficacy against cervical cancer. Complete prevention of virus infection, referred to as sterilizing immunity, was also demonstrated by the HPV vaccine, breaking another dogma that considered this an elusive goal.

Vaccine redemption

Despite its extraordinary effectiveness in preventing cervical cancer, the HPV vaccine had to fight some initial backlash caused by prejudice and confusion. 

“HPV being a sexually transmitted disease overshadowed the importance of this vaccine as a cancer prevention strategy, which is far more significant and the ultimate goal of vaccination,” said Munjal, who is a pediatric infectious disease doctor. “This vaccine was 90% effective against HPV and we had so much joy because it can eventually eradicate HPV-related cancers. But we just saw the numbers and missed the story. We had to get back to basics and normalcy regarding this vaccine. Pediatricians had to give this vaccine as they did the rest of the recommended vaccines — treat it exactly the same. It’s a revolutionary change that we’ve lived through and learned from.”

That the vaccine protected against cancer and genital warts made it a hot button issue tied to sexually transmitted disease and the myth that the vaccine would somehow encourage or endorse promiscuity among teenagers.

Munjal also discussed different vaccine rollout strategies in other countries.

“Right now HPV vaccine uptake is at 50%, but in Australia and the United Kingdom, the disease burden is dropping,” said Munjal. “By 2030, Australia will cure cervical cancer by 90%. They were able to do it because it’s a school-based health campaign which shows the effectiveness of bringing care to where people are.”

In 2006, Merck’s HPV vaccine Gardasil was approved in the U.S. It protects against HPV types 6, 11, 16 and 18, preventing 70% of cervical cancers, and the majority of HPV-induced cancer cases and genital warts. In 2014, an expanded vaccine Gardasil 9 was approved.

One of the most important advances in cancer prevention, the HPV vaccine is safe and effective. It is recommended for people from 11 to 26 years old and available to adults up to 45 years old who are at risk. Yet, vaccine rates in the U.S. for girls and boys from 13 to 17 years old still hover between only 48.6% to 51%1. About 14 million people contract HPV each year in the U.S., and 92% of these infections are caused by vaccine-preventable strains¹.  

The United States has the capability to eradicate HPV and by doing so has the opportunity to wipe out cervical cancers and six other cancers related to HPV. We still need new methods to screen for HPV and improve treatment on pre-cancerous lesions. The Healthy People 2020 campaign wants complete vaccination for more than 80% of female and male teenagers ages 13-15 by 2020⁴. 
 

1. Centers for Disease Control (CDC)
2. International Agency for Research on Cancer (IARC)
3. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. 1999 Walboomers J.M. et al, J Pathol.
4. healthypeople.gov

At the latest installment of Wistar’s Women & Science Program, guest speaker Dr. Padmanee Sharma, a distinguished clinician and researcher who has focused her career on understanding how to boost the human immune system to treat cancer, shared her personal and scientific journey to reaching the forefront of her field.

Born to immigrant parents of Indian descent in Guyana, who later fled the country due to political and religious turmoil and arrived with few resources in the U.S., Sharma chased “her American dream” supported by the strong women in her family, who encouraged her passion for science and medicine.

Dr. Sharma relayed how she had to work harder and more efficiently than many to succeed, though her path was guided by strong forces: a passion for immunology, a healthy dose of ambition, a can-do attitude, and mentors who believed in her. 

“Women are oftentimes faced with a dismissive attitude,” Sharma said. “But in the end, what proves your value is the ability to deliver on your ideas.”

Sharma’s immunology research coincided and contributed to the inception of the immunotherapy revolution, when the immune checkpoint pathways had just been discovered as the “brake pedals” that control our immune responses. This suggested the idea that checkpoint inhibitor blockade therapy could “take the foot off the brake pedal” and unleash the full antitumor potential of our immune system. 

“This was a paradigm shift in cancer therapy,” said Sharma. “For the first time, we were able to cure patients and achieve long-term remission.”

Pushing back initial skepticism, Sharma ran the first pre-surgical immunotherapy clinical trial, proving the idea that access to pre- and post-treatment tissue samples provides a deeper insight into the antitumor mechanisms of immunotherapy. Today, her research strategy reflects this model, with a continuous crosstalk between clinical observations and basic research.

“We need to design clinical trials that are guided and backed by strong science and, at the same time, use what we learn in patients to steer our basic research in the right direction.”

As a mother of three girls, a professor, principal investigator and the co-director of the Parker Institute for Cancer Immunotherapy at The University of Texas MD Anderson Cancer Center, Sharma’s life is very busy. 

“There is no perfect balance recipe that applies to everyone,” she said. “We need to figure out what works best for us while being respectful of other people’s choices.” 

In her case, success is based on following her vision, building a strong team and finding a loving partner who celebrates her passion. 

Getting sick with these childhood diseases could mean much more than a fever and a rash.

A brief history of vaccination

Infectious diseases have existed alongside (and within) humans throughout history. Efforts to prevent contagion have been attempted since before the discovery of our immune system and the pathogens that try to invade it.

The practice of immunization is based on the idea of exposing the body to a weakened or dead infectious agent (or part of it) to induce a mild version of the disease that the host is able to fight off, remaining protected at the next encounter.

Variolation—injecting material from a smallpox patient’s sore into a healthy person’s arm to protect against smallpox—was common practice starting in the 17th century in China, the Middle East and Africa, and well before Edward Jenner created the first modern vaccine in 1798.

Jenner observed that milkmaids who had been infected with vaccinia virus (the cause of cowpox in cows) did not get sick with smallpox. He was able to achieve immunization against smallpox by inoculating people with the vaccinia virus—hence the terms “vaccination” and “vaccine.”

This first empiric vaccine laid the foundation for the development of many other vaccines over the course of the 19th century. Scientists fine-tuned the technology to make vaccines safer and more effective. In the 20th century, isolation of many infectious agents together with progress in immunology, cell culture and molecular biology, allowed for the advent of more vaccines that have saved millions of lives and changed the course of human history.

Spotlight on the mumps, measles and rubella vaccine (MMR)

The Wistar Institute developed the rubella vaccine that is currently given to children in the U.S. and many other countries as part of the MMR trivalent vaccine, which provides protection against mumps, measles and rubella.

Licensed by Merck in 1971, this vaccine combined the three existing vaccines into one and dramatically curbed three childhood infections that affected millions in the pre-vaccine era and were associated with severe complications and death. The Wistar rubella vaccine is also contained in the MMRV vaccine ProQuad licensed by Merck and approved in the U.S. in 2005, which also protects against varicella virus (chickenpox).

MEASLES

Measles is a highly contagious disease that causes fever, respiratory symptoms and a rash. In a small percentage of cases, it can result in serious complications and death, especially in young children, pregnant women and immunocompromised individuals. Complications include pneumonia, which is the most common cause of death from measles in young children and occurs in one out of every 20 infected children; encephalitis, or swelling of the brain, that can lead to convulsions, deafness or intellectual disability and affects one child out of every 1,000 infected; and premature or low-birth-weight babies in pregnant women.

The rubeola virus that causes the measles was isolated in 1954, after which several generations of vaccines were developed. In 1968, the final (and current) version of the attenuated vaccine was created and since then has contributed to measles cases plummeting in the U.S. In 2000, endemic measles was declared eliminated. Yet in recent years measles has returned with several outbreaks happening in the U.S. and beyond, linked to falling immunization rates in certain groups.

MUMPS

Mumps is a very contagious viral infection that manifests with swelling and pain in the salivary glands, fever, headache, muscle aches, and fatigue. In the vast majority of cases mumps causes very mild symptoms, but in rare cases it can lead to serious complications. These include meningitis, an inflammation of the brain and spinal cord membranes; hearing loss; encephalitis; and orchitis, or the inflammation of testicles, which occurs in one third of boys infected with mumps.

In 1963, the mumps virus was isolated, and a vaccine was licensed in 1967 that has contributed to a more than 99% decrease in mumps cases in the U.S.

RUBELLA

Rubella, or German measles, usually manifests with mild symptoms and a red rash but is associated with severe complications in pregnant women, known as congenital rubella syndrome (CRS). CRS can cause miscarriage, stillbirth and birth defects such as heart problems, loss of hearing and eyesight and intellectual disability.

In 1964, a major rubella outbreak started in Europe, crossed the Atlantic Ocean and swept into the U.S., infecting 12.5 million, killing 2,000, causing 20,000 cases of CRS, and leading to thousands of miscarriages and children born with birth defects.

The first rubella vaccines used in the U.S. were licensed in 1969/1970. At the same time, another vaccine developed at Wistar in the laboratory of Stanley A. Plotkin, M.D., was licensed in Europe. The Wistar-developed vaccine proved to be more effective and have a better safety record than the others, leading the U.S. to switch in 1979. Plotkin’s vaccine is still used today and is the only rubella vaccine currently licensed in U.S.

With critical support from the Bill & Melinda Gates Foundation, Wistar is now working with external collaborators to expand and archive the research-grade rubella virus seed stock in order to provide companies with GMP materials to produce new vaccines, increasing distribution around the world and bolstering supply security.

Measles resurgence

The MMR vaccine is very effective against measles: two doses are about 97% effective while one dose is about 93% effective. Yet, measles has been on the rise globally, leading to a public health alert. The World Health Organization reported that there were more cases of measles in the first half of 2019 than in any year since 2006. In the first half of 2019 in the U.S. alone, there have been 1,182 measles cases across 30 states—a high in the last 25 years.

There are many reasons for this resurgence. Because measles is highly contagious, it is estimated that 95% of people need to be vaccinated in order to protect the population from outbreaks—a concept called herd immunity. Current U.S. vaccination rates are holding around 91% and more children in Europe are being vaccinated than ever before, but these rates are still under the required threshold, therefore the population is still vulnerable to outbreaks.

Vaccination rates and measles outbreaks

But why is the measles resurgence happening now if the vaccination coverage has been stable or improved in recent years? This could be partly due to the nature of highly contagious diseases that tend to spread in wave-like cyclic patterns.

On the other hand, statistical and epidemiological analysis indicate a correlation between a decrease in vaccination coverage and measles outbreaks. In fact, several outbreaks have been reported in close-knit communities with particularly low vaccination rates due to vaccine skepticism or refusal for religious or philosophical reasons. In those cases, travelers brought measles back from other regions where large outbreaks were occurring, and infection spread fast among unvaccinated people.

Healthcare inequality also puts children in medically underserved families at higher risk of infection.

Therefore, while measles has a tendency to resurge in populations with a lower than 95% vaccine coverage, pockets where vaccination rates are lower than the nation’s average offer breeding ground for the virus to spread undisturbed.

MMR safety

Rigorous studies have confirmed that the MMR vaccine is very safe and overwhelmingly debunked reports of any association with autism in children.

As with all medicines, vaccines may have side effects. The MMR vaccine has been associated with mild and temporary side effects including rash, fever and headache. More serious adverse events, including seizures, are very rare and not associated with long-term effects. Allergic reactions are also rare. The risk to benefit ratio is such that getting the MMR vaccine is much safer than getting measles, mumps or rubella.

The TP53 gene is the most frequently mutated gene in human cancer. In addition to mutations, this gene comes in numerous variations in the human population. Some of these variations alter the function of the p53 protein. 

A collaborative study from the Dotiwala and Murphy laboratories discovered that a rare, African-specific variant of TP53 called P47S causes iron accumulation in macrophages and other cell types and is associated with poorer response to bacterial infections, along with markers of iron overload in African Americans.  

According to the study, published online in Nature Communications, macrophage iron accumulation disrupts their function, resulting in more severe bacterial infections. It also causes macrophages to have antinflammatory properties.

Interestingly, the P47S variant improved response to malaria in mice. Researchers injected them with the malaria toxin and observed a less severe disease than in mice that carry the common p53 variant. Acute malaria is a highly inflammatory disease, therefore the antinflammatory activity of P47S macrophages limits disease severity in mice. The authors hypothesize that this effect of the P47S p53 variant could help people survive in malaria-endemic regions. 

This study may help understand the connection between the P47S TP53 gene variant and iron overload disorders as well as the increased occurrence of certain bacterial infections and cancers found in African Americans.

     The Zhang laboratory continues to make strides in ovarian cancer research. In a paper published in Cancer Cell the team described a novel therapeutic strategy based on combining EZH2 inhibition and PARP1 inhibition. 

PARP inhibitors are used as a maintenance treatment in women who carry genetic mutations that cause impaired DNA repair ability. Therefore, tumors with functional DNA damage repair do not typically respond to this therapy.

The lab researched a strategy to expand the use of PARP inhibitors to benefit a larger group of women whose tumors don’t have defects in DNA repair. They found that another class of inhibitors called EZH2 inhibitors render cancer cells vulnerable to PARP inhibitors in ovarian cancers with overexpression of the CARM1 oncogene. The study suggests that PARP inhibitors and EZH2 inhibitors may be used in combination as a precision treatment strategy for ovarian cancer.

In a second study, published in Nature Communications, Zhang and colleagues discovered a novel pathway involved in cellular senescence that controls inflammation and response to cancer immunotherapy.

Cellular senescence is a natural tumor suppression means that stably halts proliferation of damaged or premalignant cells, for example after chemotherapy. Senescent cells also produce an array of inflammatory molecules that trigger inflammation and immune reaction.
 
The newly discovered pathway enables detection of DNA in the cytoplasm, which is a signal of DNA damage, and controls inflammation and cellular senescence. This pathway may be targeted to affect cancer cell response to checkpoint inhibitors during chemotherapy.