Vaccines in the Pipeline

VACCINES HAVE LONG been one of the world’s most cost-effective and potent means of fighting disease. The eradication of polio in the United States and the global eradication of smallpox are but two examples of the revolutionary results vaccines achieved. It’s no surprise, then, that vaccine development remains a crucial aspect of pharmaceutical research.

This year could be full of exciting breakthroughs, although some of the most anticipated vaccines could still be years away. However, even the perceived failures of last year can further researchers’ knowledge and experience. And, most researchers, among others who long for disease prevention, are hopeful past letdowns will fuel 2018’s successes.

Here are a few of the most promising vaccines in the pipeline for HIV, type 1 diabetes, influenza, cancer, Clostridium difficile (C. diff) and Ebola. Time will tell whether the current trials will result in a tried-and-true product, but several studies look positive so far.

HIV

Although current HIV treatment is successful because antiretroviral therapies have prevented the virus from being the death sentence it once was, such treatments are still expensive and hard to tolerate for some. They are also difficult to obtain. In fact, only around half of the 37 million people who live with HIV worldwide are able to obtain therapy. Many who suffer from the illness are not even aware they have it, and around two million new cases are reported globally each year. 1 Having a vaccine to prevent HIV would be ideal because it could eliminate the need for long-term treatment and the disease entirely.

But developing such a vaccine is not easy, as several failed attempts have shown over the years. Still, there is always hope. In Seattle, Wash., last year, scientists at Fred Hutchinson Cancer Research Center launched an investigational study of a “mosaic” HIV-1 preventive vaccine on World AIDS Day. The human trials began after successful animal trials, and much excitement revolves around the project. The HIV Vaccine Trials Network (HVTN), headquartered at the Fred Hutchinson Seattle campus and affiliated with the research, has launched a record four HIV vaccine clinical trials over the last year.¹

Among these was the Imbokodo clinical trial in South Africa, which is a site using the HIV-1 vaccine. Sponsored by Janssen Pharmaceutical Companies, a division of Johnson & Johnson, and funded in part through the Bill and Melinda Gates Foundation and the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID), 1 the vaccine offers perhaps the most promising research to end the HIV pandemic. It has reduced the risk of infection by 94 percent during each exposure and resulted in 66 percent complete protection after six exposures.²

The term “mosaic” stems from the variety of genes taken globally from several HIV subtypes. The study’s goal is to initiate a far-reaching immune response that could fight any variety of the virus regardless of its origin in the world. Through the mosaic concept, Frank Tomaka, MD, a study co-chair, says, “what we’re aiming for is a global vaccine. HIV preventative vaccines are difficult because the immune responses that may protect against one subtype may not work against another. Our goal is to produce one vaccine that can be shipped everywhere and can be efficacious everywhere.”¹

Another outstanding HIV vaccine trial underway is HVTN 702, which began in November 2016, enrolling 5,400 HIV-negative South African men and women. Results are slated for late 2020. Should the vaccine provide at least 50 percent protection against the HIV virus, it could become the first licensed vaccine used against the disease.¹ These and several smaller studies are providing researchers with increasing hope that HIV will soon be a thing of the past.

According to HVTN founder and leader LarryCorey, MD, “We are in the midst of an unprecedented time in HIV vaccine research. We have four concurrent efficacy trials underway, which will collectively enroll 12,200 volunteers in the search for an HIV vaccine over the next few years. With the support of our funders and research partners, we are doing all that we can to honor loved ones taken from us too soon and drive the progress that will secure a future without HIV.”¹

Type 1 Diabetes

More than two decades of research at the University of Tampere in Finland has demonstrated evidence linking a type of enterovirus called coxsackievirus B1 with an autoimmune reaction that causes the body to destroy cells in its own pancreas, leading to the development of type 1 diabetes.³

In one study on mice, researchers at Tampere and at Swedish medical university Karolinska Institutet have shown the enterovirus vaccine can protect against this virus-induced type 1 diabetes. Although the exact origin of type 1 diabetes is yet unclear, enteroviruses have long been thought to be a potential cause. In the study, researchers tested the virus’s involvement in diabetes development by testing a prototype vaccine. At-risk individuals who are vaccinated are monitored for the onset of diabetes. If enteroviruses are involved and the vaccine is successful in preventing disease onset, such a vaccine will become a preventive treatment for virus-induced diabetes. It could also lead to the development of other vaccines for the non-virus-induced form of the illness.

So far, the data seem hopeful. Professor Malin Flodström Tullberg at the Karolinska Institutet says, “These exciting results showing that the vaccine completely protects against virus-induced diabetes indicate the potential that such a vaccine has for elucidating the role of enteroviruses in human type 1 diabetes.” Vesa Hytönen, MD, a prototype vaccine developer, adds that “the model described in this paper provides an excellent platform to test further enterovirus vaccines which contain a greater number of potential diabetogenic viruses. Through these proof-of-concept studies, we hope to develop and experimentally validate an enterovirus vaccine similar to the commonly used poliovirus vaccine, which has the potential to establish whether enteroviruses play a role in type 1 diabetes.”³

Tampere professor Heikki Hyöty, another study author and a pioneer in such research, explains: “The experiments here are important steps toward the clinical use of novel enterovirus vaccines. Such a vaccine is under further development by Vactech Ltd. and its collaborator Provention Bio for testing in a clinical setting.” Professor Hyöty adds that the investigational vaccine is not a cure for those who already have diabetes, but researchers are hopeful if trials are successful the vaccine could be preventive.³ “Already now it is known that the vaccine is effective and safe on mice,” explains Hyöty. “The developing process has now taken a significant leap forward, as the next phase is to study the vaccine in humans.”⁴

Beyond preventing virus-induced type I diabetes, the vaccine could also help to prevent other enterovirus infections. “Additionally, the vaccine would protect from infections caused by enteroviruses such as the common cold, myocarditis, meningitis and ear infections,” says Hyöty.⁴

Researchers at the University of Tampere are also working to create a vaccine that targets a greater number of viruses thought to cause type 1 diabetes, beyond enterovirus. They are slowly providing more proof that viruses are implicated in the development of diabetes, and they are excited to begin clinical studies in humans. 3 And, while the leap from mice to humans is great, researchers are hopeful because of what they’ve experienced thus far.

Universal Flu Vaccine

The 2017-18 influenza (flu) season was one of the worst on record. 5,6 Each year, the flu virus takes its toll on patients and caregivers, and vaccines to date seem hit-or-miss at best in their efficacy since the number of strains they are designed to prevent is limited. But, that could soon change. Knowing the financial and personal damage the flu causes, finding a vaccine that could prevent all of its strains is a never-ending quest for some researchers. And, it seems they are moving closer to a solution.

Scientists at the University of California, Los Angeles (UCLA) claim they may have discovered a so-called “Goldilocks” flu vaccine. Studies so far indicate a strong immune response in animal subjects, but without causing the illness. The developmental vaccine rallies T cells to fight the disease, which is crucial because, unlike previous vaccines that employ only antibodies specific to certain strains, T cells will fight any form of flu virus.⁷

The vaccine is also different from others because it uses a live virus that elicits an antibody response and a T cell immunity in mice and ferrets, and it’s hoped this finding will transfer to humans. Typically, flu vaccines use a dead virus that causes no T cell response. “This is really exciting,” said Kathleen Sullivan, chief of the division of allergy and immunology at the Children’s Hospital of Philadelphia. “It has the magic of both great antibody response and inducing a strong, strong T cell response that will be a safety net — so if a virus breaks through the first line of defense, you will have T cells to make sure you don’t get very sick.”⁷

UCLA is not alone in its quest. NIAID is also pursuing a multi-strain flu vaccine “that provides robust, long-lasting protection against multiple subtypes of flu, rather than a select few.” According to the NIAID website, “Such a vaccine would eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains, potentially including those that could cause a flu pandemic.”^8,9

Cancer

Researchers at Stanford University are thrilled by recent studies in mice that show a human cancer vaccine could actually be possible, although it will take much more time and effort. They found “injecting trace amounts of immune-stimulating agents into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases.” The method, which activates T cells, could work for multiple kinds of cancer, including those that occur spontaneously.

Currently, the researchers are recruiting lymphoma patients for human clinical trials. They believe applying the agents locally in small amounts could be a fast-acting and cost-effective cancer therapy that will not cause adverse side effects caused by current cancer treatments. “When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells. All of these immunotherapy advances are changing medical practice. Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, body-wide effects, including the elimination of tumors all over the animal.”¹⁰

Beyond this trial, there is even more hope for a cancer vaccine, though a somewhat different type. Researchers at the University of Pennsylvania and the Lausanne Branch of the Ludwig Institute for Cancer Research in Switzerland, among other institutions, are making progress toward a cancer vaccine that is specifically designed for each patient’s disease and tumors. While the research is fledgling, the results are impressive so far.¹¹

Lead study author Janos L. Tanyi, MD, PhD, and his team examined immune cells in patients’ blood to develop the vaccines, extracting patients’ dendritic cells, combining them with pieces of patients’ tumors and activating them with interferon gamma. The cells were then injected into patients’ lymph nodes. Twenty-five advanced ovarian cancer patients underwent this procedure, each getting a dose of the dendritic cell mixture every three weeks, with some study participants in the program for two years. The study’s purpose was merely to determine whether the treatment was possible and safe, but the scientists are still encouraged by the results.¹¹

One participant, a 46-year-old woman who had already received five courses of chemotherapy for her cancer prior to the study, received 28 doses of the personalized vaccine over the course of two years and remained in remission for five years. “The two-year overall survival rate of these responder patients was 100 percent, whereas the rate for nonresponders was just 25 percent,” said Dr. Tanyi. “The idea is to mobilize an immune response that will target the tumor very broadly, hitting a variety of markers, including some that would be found only on that particular tumor.”11 The vaccine appears to be safe and merits much more research and testing in larger clinical trials.

C.Diff

Most often contracted in hospitals and other medical settings, C. diff can mean a brutal, if not life-threatening, bout with intestinal inflammation, fever, nausea and diarrhea for those who contract it. Thankfully, Pfizer has had success with its experimental C. diff vaccine in the recent past. The company’s vaccine candidate is designed to help prevent C. diff infection by inducing a functional antibody response capable of neutralizing the two main disease-causing toxins produced by the infection (toxins A and B).¹²

Today, because of the vaccine’s good initial results, the Clover trial, a clinical research study on humans for the developmental vaccine, is recruiting adults 50 years and older who are at risk of developing the infection. The study will determine how well-tolerated and efficacious the vaccine is. Each subject who is admitted to the study will receive the vaccine, then three doses of the C. diff vaccine or a placebo. They will then be followed for up to three years as researchers watch for potential C. diff infection.¹³

While the vaccine’s efficacy is obviously still uncertain, researchers are very hopeful. Kathrin Jansen, PhD, senior vice president and head of vaccine research and development for Pfizer Inc., said, “We are very encouraged by these interim immunogenicity and safety results demonstrating robust increases in vaccine-elicited neutralizing antibodies to both toxins that we believe could provide protection against C. difficile disease.”¹²

Ebola

Just recently, a study published in The Lancet Infectious Diseases indicates participants inoculated with an experimental Ebola vaccine still maintain high and stable levels of antibodies to the Ebola Zaire virus two years after vaccination (there are other strains of Ebola). Participants who received a high dose of vaccine typically had higher antibody levels, but even those who received a lower dose showed promising levels that could potentially resist the disease.

The vaccine, V920, is from Merck and is given in a single shot, which is easiest for many African regions. “The ideal vaccine in these regions would have long-term durability,” explains Angela Huttner, MD, lead author of the paper and an infectious diseases specialist at Switzerland’s University Hospitals of Geneva. “This is really good news because this vaccine is destined for places where logistics are very difficult. Having to do booster shots would be very impractical in these regions.”

Merck is working to obtain a 2018 licensure filing with the U.S. Food and Drug Administration for V920. It is also pleased with the results: “This publication is the first demonstration of the durability of the antibody responses induced by V920 out to two years. We are encouraged by these important results, and testing of long-term follow-up samples from additional trials is planned or ongoing to corroborate these findings.”¹⁴

It is too early to know whether the vaccine will offer lifelong immunity, but research is certainly inching closer to that goal.

The Coming Results

While no one can predict success or failure in vaccine development, or any type of research for that matter, the mere fact scientists are tirelessly pursuing answers is heartening. No research is wasted, although not all research results in a viable vaccine. Let’s hope 2018 and 2019 bring a wealth of knowledge and disease prevention alike, as well as some newly licensed vaccines that will improve, or even save, many lives.