New Vaccines in Development

For more than 200 years, vaccines have protected people from serious and often lethal diseases that have historically hindered their freedom and productivity. And, each year, researchers further develop new, life-changing and often lifesaving  vaccines that make our quality of life more sustainable. Although not a magic bullet, vaccines offer a solid protective buffer from disease that everyone can celebrate.   

While COVID-19 vaccine research and production have dominated headlines and kept scientists working overtime for more than a year, other exciting and crucial vaccines in the pipeline warrant attention. Possibilities in the making for the near future include urinary tract infections, super gonorrhea, staphylococcus aureus, tick-borne encephalitis, HIV, malaria and cancer vaccines. And, while only time will tell whether the current research and trials will result in effective products, endeavors look positive. 

Urinary Tract Infections (UTIs)

Scientists at Duke University Medical Center have developed a vaccine strategy to prevent UTIs. In mouse models, the strategy clears the bacteria responsible for causing UTIs and reprograms the immune system to fight off the bacteria that could cause future infections. The researchers found bladder-immunized mice fought off E. coli and eliminated all residual bladder bacteria. And, while this is significant for all, it is especially so for women who experience recurring UTIs that require repeated rounds of antibiotics. According to lead author of the study Jianxuan Wu, PhD, “The new vaccine strategy attempts to ‘teach’ the bladder to more effectively fight off the attacking bacteria. By administering the vaccine directly into the bladder where the residual bacteria harbor, the highly effective vaccine antigen, in combination with an adjuvant known to boost the recruitment of bacterial-clearing cells, performed better than traditional intramuscular vaccination.” 

Soman Abraham, PhD, senior author of the paper, states, “Although several vaccines against UTIs have been investigated in clinical trials, they have so far had limited success.… Our study describes the potential for a highly effective bladder vaccine that can not only eradicate residual bladder bacteria, but also prevent future infections. We are encouraged by these findings, and since the individual components of the vaccine have previously been shown to be safe for human use, undertaking clinical studies to validate these findings could be done relatively quickly.”¹ 

Super Gonorrhea

For roughly 14 years, gonorrhea has shown signs of becoming “supercharged,” or resistant to antibiotics.² Considering how prevalent gonorrhea has become in recent years, this is dire news. The Centers for Disease Control and Prevention (CDC) estimates approximately 1.6 million new gonococcal infections occurred in the United States in 2018, and more than half occur among young people age 15 years to 24 years.³ The World Health Organization (WHO) estimates roughly 78 million people per year are infected with gonorrhea globally. Of U.S. cases, an estimated 550,000 involve drug-resistant bacteria. Drug-resistant Neisseria gonorrhea is identified by WHO as a “priority” pathogen, and it is said to be an “urgent” public health threat that requires aggressive action by CDC.⁴

CARB-X (Combating Antibiotic-Resistant Bacteria), a Boston University-based nonprofit dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria, has awarded Oxford University’s Jenner Institute $2 million to develop a vaccine to combat the sexually transmitted gonorrhea infection. The vaccine, labeled dmGC_0817560 NOMV, consists of fluid-filled blisters from the outer surface of gonococcus. The goal is for the vaccine to induce protective immunity against gonorrhea that will prevent individuals from developing the disease and also interrupt the spread of antibiotic resistance found in gonococcal bacteria. The project is currently in lead optimization, a crucial early development phase in which the most promising preclinical vaccine candidate is identified. It is hoped a clinical trial phase will be reached by 2024. Working alongside the Oxford Vaccine Group, researchers also aim to produce an affordable vaccine for global use.⁴

Staphylococcus 

CARB-X is also funding Affinivax to develop a vaccine to prevent Staphylococcus aureus (S. aureus), the most common form of staph infection, which is a serious threat to hospital patients and the immunocompromised, among others. In 2017, an estimated 119,247 S. aureus bloodstream infections, with 19,832 associated deaths, occurred in the United States.⁵ 

Affinivax’s S. aureus vaccine candidate will be funded through Phase I testing and will use the company’s multiple antigen-presenting system (MAPS) vaccine technology platform. The vaccine is designed to “induce a B-cell protective immune response to multiple highly conserved staphylococcal protein antigens.”⁶ It will also induce Th17 and Th1 responses against each of the protein antigens the vaccine introduces. This offers the possibility for protection not only against invasive staphylococcal infections, but also from a reduction in mucosal colonization by the bacteria, which is often the first step in pathogenesis. 

Preclinical data from a lead MAPS S. aureus vaccine candidate developed at Boston Children’s Hospital have shown that impacting multiple immune pathways with a single vaccine offers the potential for both robust and broad protection from S. aureus infection. In preclinical studies, the protein antigens induced B-cell responses that led to a reduction in mortality following invasive disease challenge, Th1 or Th17 responses that led to prevention of skin abscesses and the clearance of bacteria from the gastrointestinal tract, and both B-cell and T‑cell responses that contributed to the prevention of dermonecrosis.⁷ 

In addition to Affinivax’s efforts, Cologne University Hospital and the German Center for Infection Research are partnering to develop another possible S. aureus vaccine after decades of research. Initially, they characterized several S. aureus antigens as potential vaccine candidates. With the help of monoclonal antibodies that had exhibited a protective effect in the infection model, Alexander Klimka, PhD, first author of the German study, was able to locate their binding sites, known as epitopes, in the vaccination antigens.⁶ As Dr. Klimka explains, “For the S. aureus protein coproporphyinogen III oxidase (CgoX), we were able to narrow the epitope to a section comprising 12 amino acids. What makes this work special is that it has been possible with this extremely small section of CgoX to trigger a protective immune response against the S. aureus infection. Narrowing the vaccine to a small epitope of 12 amino acids constitutes an unprecedented precision of a vaccine candidate against S. aureus.”

It is especially hopeful that more than 97 percent of the more than 35,000 researched clinical strains of S. aureus feature this epitope unchanged and that this vaccine candidate will therefore have a wide-ranging effect. According to Martin Krönke, PhD, director of the Institute for Medical Microbiology, Immunology and Hygiene at Cologne University Hospital, “Epitope-focused immunization represents a new quality in vaccine development because far fewer adverse immune reactions can be anticipated than those observed occasionally for the use of total proteins or even inactivated pathogens.”⁸

Tick-Borne Encephalitis (TBE)

While not common in the United States, between 5,000 and 12,000 cases of TBE are reported in Europe each year alone, primarily in the Baltic states.⁹ Other cases of TBE are found throughout Asia, including China and Siberia. TBE often requires hospitalization since the disease attacks the central nervous system with the potential to cause long-term neurological symptoms and death.¹⁰ 

To prevent TBE, Pfizer’s vaccine, TicoVac, has been used for more than 40 years outside the U.S., and more than 160 million doses of it have been distributed since 1976. Yet, the vaccine has only very recently received U.S. Food and Drug Administration (FDA) approval for priority review, thus promoting its potential to save many American travelers thousands of dollars in medical expenses and sick time while easing fears of severe illness. The vaccine is effective in individuals 1 year of age and older. “For many years, our TBE vaccine has helped protect millions of people in Europe from this potentially serious disease,” says Nanette Cocero, PhD, global president of vaccines at Pfizer Inc. “We are proud that today’s U.S. FDA priority review acceptance acknowledges the potential value that our vaccine candidate can bring. If approved in the U.S., we hope this vaccine will help protect those traveling to or residing temporarily in at-risk locations, potentially including military personnel who are serving overseas.”¹¹

HIV

Approximately 1.2 million people in the U.S. are living with HIV today, some 14 percent of whom (one in seven) don’t know it and need testing. According to the latest estimates from CDC, approximately 36,400 new HIV infections occurred in the United States in 2018. And while annual infections in the U.S. have been reduced by more than two-thirds since the height of the epidemic in the mid-1980s, CDC data indicate progress has stalled in recent years, with about 38,000 new HIV infections each year occurring between 2014 and 2018. The latest estimates indicate effective HIV prevention and treatment are not adequately reaching those who could most benefit from them, and certain groups such as men who have sex with men, transgender persons, African Americans and Hispanics/Latinos continue to be disproportionately affected.¹² 

In April, a Phase I clinical trial showed a new HIV vaccine resulted in a 97 percent response rate. In the trial involving 48 adult volunteers, the vaccine successfully stimulated the production of rare immune cells needed to generate antibodies against HIV, which causes AIDS and interferes with the body’s ability to fight infections. While a 97 percent response rate is exceptional, it is important to note this Phase I study represented only a small group of subjects.

According to The European Pharmaceutical Review, the vaccine is meant to act as an immune primer that triggers the activation of cells via a process called “germline-targeting.” Its purpose is to act as the first step in a vaccine regimen that would elicit the production of a variety of broadly neutralizing antibodies. Stimulating this type of response has been pursued in HIV research for decades because it could target a wide range of HIV variants. Much like the coronavirus, the surface of HIV has proteins called spikes. Antibodies generated by a future version of this vaccine would disable them from entering human cells.

The next phase of clinical trials will begin to incorporate technology developed by Moderna, which was also used in Moderna’s COVID-19 vaccine. If this vaccine is approved, it could become the first stage of a multistep strategy to combat HIV and other viral diseases.¹³

Malaria

Each year, approximately 210 million people are infected with malaria, a mosquito-borne infectious disease, and about 440,000 people die from it, the majority of whom are young children in Africa. In fact, malaria has caused four times as many deaths as COVID-19 over the past year. Each year, billions of dollars are spent on bed nets, insecticide spray and antimalarial drugs to prevent this fatal disease. But now, research shows effective vaccines against malaria could be closer than ever. In one recent clinical trial, a vaccine has prevented the disease 77 percent of the time. And, while WHO’s target efficacy for malaria vaccine is greater than 75 percent, this level has never been reached until now.

A multinational group of researchers led by professor Halidou Tinto who is based in Ouagadougou, Burkina Faso, studied the new R21 malaria vaccine in 450 children and found it to be safe and effective in those aged 5 months to 17 months. In the trial, 105 of the 147 children who received a placebo contracted malaria. But, of the 292 who received a dose of the vaccine, only 81 contracted the disease. A new Phase III trial that will test the safety and efficacy of the vaccine in a much larger number of people was due to start in four African countries in late April, aiming for accelerated approvals if successful. Manufacturing of the vaccine is ongoing at the Serum Institute of India, the world’s largest vaccine supplier. The vaccine uses a chimpanzee adenovirus called ChAdOx1 for delivery, a technology previously tested for use against malaria.¹⁴

In other malaria vaccine research, Yale scientists recently filed a patent for a malaria vaccine using a RNA platform. This new vaccine, generated by Richard Bucala and Andrew Geall is an saRNA (similar to mRNA, but more efficient) vaccine that encodes the PMIF that plasmodium normally uses to disarm our immune system. Plasmodium MIF stands for cytokine macrophage migration inhibitory factor, whose job is to regulate the movement of immune cells to the site of an infection. As Bucala and Geall discovered, immunizing patients with saRNA that encodes PMIF uses the parasite’s own gene against it and confers protection. These results were also seen in a study from 2018, in which MIF was tested successfully as a treatment for malaria infection in a mouse model.¹⁵

Cancer

A personalized cancer vaccine, PGV-001, developed through a Mount Sinai computational vaccine pipeline platform, called OpenVax, is showing benefit, is well-tolerated and has raised no safety concerns. An investigator-initiated Phase I trial showed the vaccine could benefit patients who have various cancers that have a high recurrence rate, including lung and bladder cancer.

In the trial, the team of researchers sequenced each patient’s tumor and germline DNA and tumor RNA. They then identified the tumor-specific target to help them predict whether the patient’s immune system would recognize vaccine targets. OpenVax helped researchers identify and sort immunogenic targets to synthesize and use in the vaccine. 

The trial participants statistically had a high chance of disease recurrence before the vaccine. Thirteen patients received the Mount Sinai vaccine: 10 had solid tumor diagnoses and three had multiple myeloma. All patients received at least seven doses of the vaccine, and 11 patients received all doses of the vaccine. After a mean follow-up of 925 days, four patients still had no evidence of cancer, four were receiving subsequent lines of therapy, four had died, and one chose not to continue the trial. The median progression-free survival from time of surgery or transplant was 618 days. The vaccine was well-tolerated, with roughly one-third of patients developing grade 1 injection-site reactions. Among the patients without evidence of disease, diagnoses include myeloma, lung, breast and urothelial cancer.

Thomas Marron, MD, PhD, assistant director for early phase and immunotherapy trials at the Tisch Cancer Institute (TCI) and assistant professor of medicine, explains, “While immunotherapy has revolutionized the treatment of cancer, the vast majority of patients do not experience a significant clinical response with such treatments.” However, he says, “Cancer vaccines, which typically combine tumor-specific neoantigens with an adjuvant that primes the immune system, may be a viable treatment strategy for patients without a pre-existing antitumor response.”

The vaccine was given with the immunostimulant poly-ICLC, which is “a synthetic, stabilized, double-stranded RNA capable of activating multiple innate immune receptors, making it the optimal adjuvant for inducing immune responses against tumor neoantigens,” said study author Nina Bhardwaj, MD, PhD, director of the immunotherapy program and the Ward-Coleman Chair in Cancer Research at Mount Sinai’s TCI.

“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” said Dr. Marron.¹⁶

The mRNA technology used to develop the Moderna and Pfizer vaccines also shows potential for developing a vaccine to kill cancerous tumors. While there are already vaccines that prevent infection with viruses that cause cancer such as the hepatitis B vaccine that prevents some types of liver cancer and the human papillomavirus vaccine that prevents cervical cancer, the flexibility of mRNA vaccines has researchers thinking more broadly about tackling cancers not caused by viruses.

BioNTech is developing an mRNA vaccine that shows promise for people with advanced melanoma. CureVac has developed a vaccine for a specific type of lung cancer, with results from early clinical trials. And, there’s promise of personalized anticancer mRNA vaccines specific to each patient’s tumor that could train the immune system to fight its own individual cancer. Several research groups and companies are working on this.¹⁷

Coming Results

While no one can guarantee success or failure in vaccine development, advances so far are encouraging. Hopefully, 2021 and beyond will bring more peace, productive research and breakthrough developments to much-needed vaccines that will change the world.