Vaccines on the Horizon

Every year, millions of people worldwide suffer and/or die from diseases for which there are no medicines. But as history has shown, when vaccines become available, they can change the course of diseases and treat, prevent or eradicate them altogether. Polio, smallpox, measles and diphtheria vaccines are prime examples of victories over disease.

Today, manufacturers are working on new and improved vaccines for many diseases — some of which the medical community has had success at preventing and treating, and others for which it has not. These vaccines are just a scant few when compared with the myriad medical conditions unanswered by vaccines, but their importance cannot be overstated. While there are hundreds of vaccines in clinical trials, the following vaccines on the horizon focus on illnesses that have been plaguing society for a considerable time.

New Vaccines on the Horizon

Malaria. Malaria is a mosquito-borne disease that causes more than 2.7 million deaths each year, according to the World Health Organization.¹ The potentially fatal blood disease is caused by a parasite that is transmitted to human and animal hosts by the Anopheles mosquito. The human parasite, Plasmodium falciparum, digests the red blood cell’s hemoglobin, and changes the adhesive properties of the cell it inhabits, which in turn causes the cell to stick to the walls of blood vessels. When the infected blood cells stick to the capillaries in the brain, blood flow is obstructed, causing a condition called cerebral malaria.

GlaxoSmithKline Biologicals and the Malaria Vaccine Initiative have partnered with scientists in African research centers to develop a vaccine against malaria. The vaccine is intended for children under the age of 5 who are most vulnerable to the disease. The Phase 3 trial of the most advanced vaccine candidate, RTS,S, begun in May, will evaluate the vaccine’s efficacy in two groups of children. The first group, ages 6 weeks to 12 weeks, will be vaccinated as part of their regular schedule of infant immunizations. The second group is children ages 5 months to 17 months.²

The Phase 3 trial builds on more than 10 years of clinical research in Africa. Recent Phase 2 studies showed that over an eight-month follow-up period, RTS,S cut the incidences of malaria in children by 53 percent and didn’t interfere with other childhood vaccinations given simultaneously. However, unlike vaccines against smallpox or measles, the malaria vaccine provides only partial protection against disease. It is unknown how long the vaccine’s protection lasts.

If the required regulatory clearances are granted and international and African national public health authorities recommend its use, RTS,S could be introduced in 2012 for children age 5 months to 17 months. Once the vaccine is recommended for use in infants, full availability is anticipated by 2014.

HIV/AIDS. Acquired immunodeficiency syndrome (AIDS) is the fourth leading cause of death globally. Every day, 7,500 people become newly infected with the human immunodeficiency virus (HIV), the cause of AIDS. To date, more than 20 million people have died from AIDS, and more than 33 million people are living with HIV. HIV is a virus that gradually attacks immune system cells, making the body more vulnerable to infections, and making it more difficult to fight off those infections. A person is said to have AIDS when they have developed a very advanced HIV infection, although that can often take years.

Testing of the first AIDS vaccine, which was developed by Merck & Co., occurred in 2007 with disappointing results. Known as the STEP Study, the trial was brought to an early end after preliminary analyses suggested that those who received the vaccine picked up HIV infections at rates higher than controls.³ Scientists hypothesized that the administration resulted in an immune response to the adenovirus that included activated helper T-cells. And, since T-cells are targeted by HIV, the vaccine effectively gave HIV more cells to infect. That hypothesis has since been disproved.

The newest HIV/AIDS vaccine was developed at the University of Cape Town in South Africa with technical help from the National Institutes of Health (NIH). The trial will seek to determine the immune response of HIV-negative people to two experimental vaccines — SAAVI DNA-C2 and SAAVI MVA-C.⁴ A trial of 12 volunteers in the United States began earlier this year. Testing on an additional 36 healthy volunteers began in July in South Africa. The trial is projected to last several years.

Cancer. Cancer represents a group of diseases that presently kills some 560,000 Americans each year. Only two cancer vaccines — for hepatitis B and genital human papillomavirus (HPV) — currently have FDA approval, and both are strictly preventive, targeting viruses that can lead to cancer. The new “therapeutic cancer vaccines” being tested are not preventive; instead, the vaccines are injected into people already inflicted with cancer in an effort to make their immune systems fight growing tumors. Four cancer vaccines have achieved positive results in Phase 3 clinical trials. These vaccines are for lymphoma, melanoma, kidney cancer, prostate cancer and colorectal cancer.

Lymphoma is a blood cancer that is often fatal. Biovest International Inc. tested its BiovaxID vaccine in a multicenter Phase 3 clinical trial, and found that the vaccine prolongs first remission duration in patients with follicular lymphoma. Biovest intends to seek approval for the vaccine in the U.S. and internationally.

Melanoma, the least common type of skin cancer, is by far the most serious form of the disease.⁵ Accounting for about 4 percent of skin cancer cases, it causes approximately 79 percent of skin cancer deaths. In the United States, the number of new cases of melanoma has more than doubled in the past 20 years. About 8,650 people in the United States are expected to die of melanoma during 2009.

Renal cell carcinoma, also known as renal cell cancer or renal cell adenocarcinoma, is the most common type of kidney cancer. The American Cancer Society (ACS) estimates that there will be about 57,760 new cases of kidney cancer (35,430 in men and 22,330 in women) in the United States in 2009, and about 12,980 people (8,160 men and 4,820 women) will die from this disease.⁶

Both melanoma and kidney cancer are the targets of the vaccine Oncophage, manufactured by Antigenics, which has received fast-track and orphan drug designations from the U.S. Food and Drug Administration (FDA).⁷ Oncophage is a therapeutic vaccine made from individual patients’ tumors. More than 800 cancer patients around the world have been treated with Oncophage in clinical trials. A Phase 3 study compared conventional treatment for melanoma versus treatment with the Oncophage vaccine, and found that the vaccine caused tumors to shrink in twice as many patients as those receiving a standard FDA-approved therapy.⁸ In 2007, results from a Phase 3 trial of Oncophage in kidney cancer showed a 45 percent improvement in recurrence-free survival associated with Oncophage in patients with intermediate-risk kidney cancer, although a significant improvement was not observed in the overall patient population. And, in 2009, interim survival data showed that Oncophage appeared to lower the risk of death by almost 46 percent in the intermediate-risk population. Final results are expected in 2010.

Prostate cancer is the most common cancer, other than skin cancers, and is the second leading cause of cancer death in American men, behind only lung cancer. The ACS estimates that during 2009, approximately 192,280 new cases of prostate cancer will be diagnosed in the United States. The ACS also estimates that 27,360 men in the United States will die of prostate cancer in 2009. Prostate cancer accounts for about 10 percent of cancer-related deaths in men.⁹

Now, after decades of failures and false starts for developing a vaccine to treat prostate cancer, a new study shows promising results.¹⁰ Provenge, manufactured by Dendreon, is a biologic drug given by infusion to spur the immune system to fight advanced prostate cancer that doesn’t respond to anti-androgen treatment. In the Phase 3 study of 512 men with advanced metastatic, androgen-independent prostate cancer, overall survival was significantly better for those for taking Provenge than those taking a placebo. Specifically, Provenge extended median survival by 4.1 months and improved four-year survival by 38 percent. Dendreon plans to submit the study’s results to the FDA in the fourth quarter of 2009; after that, the FDA will have six months to review the material.

Excluding skin cancers, colorectal cancer is the third most common cancer diagnosed in both men and women in the United States and the third leading cause of cancer-related deaths in the United States. The ACS estimates the number of colorectal cancer cases in the United States in 2009 to be 106,100 new cases of colon cancer (52,010 in men and 54,090 in women) and 40,870 new cases of rectal cancer (23,580 in men and 17,290 in women). Overall, the lifetime risk for developing colorectal cancer is about 1 in 19 (5.3 percent). It is expected to cause about 49,920 deaths (25,240 in men and 24,680 in women) during 2009.¹¹

A cancer vaccine with a twist is making headway in clinical trials at the University of Pittsburgh School of Medicine.¹² The new vaccine triggers the immune system to attack a faulty protein, MUC1, that’s often abundant in colorectal cancer tissue and precancerous tissue. It has already proven safe in patients with advanced pancreatic cancer, and is now in clinical trials to gauge the immune response it elicits in patients with a history of advanced adenomas. However, not all colorectal tumors produce abnormal MUC1, so it’s possible to develop colorectal cancer even if the vaccine is effective. Investigators have been recruiting subjects for the trial since 2008 and expect to finish gathering data in the fall of 2011.

Ear infection. Otitis media, more commonly known as an ear infection, is the most frequently diagnosed illness in children less than 15 years of age in the U.S. More than 80 percent of children will experience at least one ear infection before their third birthday. A new study conducted at Nationwide Children’s Hospital in Columbus, Ohio, shows that a pain-free vaccine could ward against ear infections.13 The vaccine was tested by placing a droplet of formula on the outer ears of chinchillas and then rubbing it into the skin. The vaccine works by prompting an immune response that reduces or eliminates NTHI, one of the bacteria commonly responsible for ear infections.

E. coli. Escherichia coli are a large and diverse group of bacteria, and while most strains are harmless, others can make individuals sick. Some kinds of E. coli can cause diarrhea, others cause urinary tract infections, respiratory illness and pneumonia, and still others are used as markers for water contamination.14 Enterotoxigenic E. coli (ETEC) is responsible for 60 percent to 70 percent of all E. coli diarrheal disease, kills two to three million children each year in the developing world, causes health problems for U.S. troops serving overseas, and is responsible for what is commonly called traveler’s diarrhea.

Now, separate studies are showing promise for a vaccine to prevent ETEC. Investigators from the Memphis Veterans Medical Center and the University of Tennessee Health Science Center described promising early results for two experimental vaccines.15 Both were largely effective at preventing E. coli from gaining a foothold in the digestive tracts of mice. The vaccines were designed to block the infection by preventing a protein at the end of the E. coli’s whip-like flagella from attaching to a second protein, known as EtpA. EtpA is secreted by the E. coli bacteria and apparently plays a role in helping the bug stick to the intestinal tract of the unsuspecting patient. The interaction between the two proteins is a key step in the infection process.

A Michigan State University researcher has developed a working vaccine for ETEC.16 The researcher’s breakthrough was discovering a way to overcome the minuscule molecular size of one of the illness-inducing toxins produced by the E. coli bug. Since the toxin was so small, it did not prompt the body’s defense system to develop immunity, allowing the same individual to repeatedly get sick, often with more severe health implications. So, he created a biological carrier to attach to the toxin that, once introduced into the body, induces a strong immune response. The vaccine was tested on mice and findings show that the biological activity of the toxin was enhanced by more than 40 percent, leading to its recognition by the body’s immune system. After immunizing a group of 10 rabbits, the vaccine led to the production of the highest neutralizing antibody ever reported for this type of the toxin. Human clinical trials could begin late in 2009.

Shigellosis. Shigellosis is endemic throughout the world, with approximately 164.7 million cases — 163.2 million in developing countries and 1.5 million in industrialized countries. Each year, 1.1 million people are estimated to die from shigella infection, and 580,000 cases of shigellosis are reported among travelers from industrialized countries. A total of 69 percent of all episodes and 61 percent of all deaths attributable to shigellosis involve children less than 5 years of age.17

Recently, the University of Maryland, Baltimore (UMB), has licensed a pediatric vaccine against shigella bacteria to PATH, an international nonprofit group, to support clinical trials, with the goal of developing a vaccine suitable for children in resource-poor countries.18 The UMB vaccine candidate is a multivalent vaccine designed to ultimately target five diseasecausing strains of the bacteria. It is hoped that when the shigella project moves to late clinical trials, a large pharmaceutical company will finalize a version of the vaccine.

Addiction. A vaccine to treat addiction is closer now than ever before, according to experts at the National Institute on Drug Abuse (NIDA).19 Research has led scientists to better understand how the addiction process works, which has led to the initial designing and testing of vaccines that may cure addiction in drug abusers and help them avoid relapses. Currently, vaccines are being looked at for nicotine, cocaine and methamphetamine addiction. The vaccines work by blocking the drug’s reward influence in the brain and producing a new conditioned behavior in addicts: If they use the drug and don’t get the high, they will learn to stop using it. None of the vaccines has been submitted to the FDA for approval. The nicotine vaccine is the closest and should be submitted in three years. A large test of the cocaine vaccine will start in the fall, with an FDA submission expected in four to five years. There’s no timetable for the methamphetamine vaccine, which is not ready for human tests.

Improved Vaccines on the Horizon

Vaccines currently exist for a host of diseases. However, due to various reasons, continued research and development for improved vaccine response is often needed. Four diseases are currently at center stage for improvement.

Neisseria meningitides (meningococcus). The recently released vaccine to prevent meningitis, Menactra (manufactured by sanofi pasteur), may soon have company. Novartis AG has developed Menveo, a vaccine to prevent meningitis that can be administered to individuals ages 11 to 55.20 In clinical trials, Menveo has been shown to elicit a protective immune response against four of the most common serogroups — A, C, W-135 and Y — of neisseria meningitides. The FDA has requested additional information on the clinical and CMC (chemistry manufacturing and control) sections of the biologics license application before it will make a decision to grant approval. No new clinical trials are required, and it is expected that Novartis will be able to respond to all questions in 2009.

Influenza. Each year, manufacturers go back to the drawing board to determine which strains of the flu virus to include in the influenza vaccine. This is determined based on information gathered over the previous year about the strains of flu viruses that are infecting humans and how they are changing. Three of several examples of improved seasonal flu vaccines include Novavax’s virus-like-particle (VLP) vaccine Phase 2 clinical trials, and Protein Sciences Corp.’s and Antigen Express’ flu vaccines which can be produced faster than had been possible previously.

Novavax’s VLP vaccine may be differentiated from other influenza vaccines in several ways.22 First, it includes three viral proteins (incorporated in the vaccine as three separate VLPs), which is important for inducing a broad immune response. In addition, the vaccine is made in cell culture rather than eggs, which permits an exact genetic match to the flu strains causing illness since there is no requirement for adapting the vaccine to grow in eggs.

Protein Sciences is among several small companies also trying to make influenza vaccines by methods that are faster than growing them in chicken eggs, the technique now generally used.23 Instead of growing whole viruses, it produces just a protein from the virus and it does so in genetically modified insect cells. The company recently has been awarded a $35 million federal grant for the development of this technology.

And, Antigen Express, a Toronto-based company, has developed a peptide vaccine which promises to be much more flexible, cost effective and rapid (taking approximately half the time) compared to the traditional way of manufacturing. The company is currently seeking funding for the development of its own H1N1 vaccine. (See the news story on Antigen Express on page 10.)

When a new strain of the flu develops that cannot be protected against by the seasonal flu vaccine, it is sometimes necessary to produce a new, secondary influenza vaccine. This is especially the case when the strain causes a pandemic, such as in the case of the new H1N1 (swine) flu. Five manufacturers are currently developing a swine flu vaccine, and as many as 160 million doses of swine flu vaccine will be available sometime in October.

One of the stirring prospects in the vaccine world involves the possibility of eradicating the flu pandemic. Sanofi pasteur has recently developed a vaccine (proven to be safe and effective in humans and ferrets) that does not need to be re-created each year to protect against different strains because the vaccine attacks an unchanging element of the virus.24

Tuberculosis. Improvements in the efficacy of the current tuberculosis vaccine are in progress. A team of Italian researchers discovered a new role for type I interferon for improving the ability of dendritic cells to stimulate an immune response against the bacterium known to cause tuberculosis.25 The researchers speculate that type I interferon may give the current vaccine the boost necessary to elicit a protection immunity against the mycrobacterium tuberculosis. According to the U.S. Centers for Disease Control and Prevention, onethird of the world’s population is infected with tuberculosis, with nearly nine million people getting sick with the disease each year. Of those nine million, almost two million will die.

The Way Ahead for Future Vaccines

What goes on behind the scenes to actually produce a vaccine ready to introduce to the market is quite complex. On average, it takes 10 to 15 years and nearly $600 million.26 The time involved includes preclinical research (synthesis and purification processes, as well as animal testing), clinical studies (Phase 1 through 3), new drug applications, reviews and approvals.27 Then, the vaccine has to be manufactured. Manufacturing biopharmaceuticals is both expensive and time-intensive, often taking two to three years.

But the lengthy process that it takes to develop vaccines may change. In July, the NIH bestowed a $13 million grant to Dr. Annie De Groot and her colleagues at the University of Rhode Island to find a way to speed the development of vaccines.28 The five-year grant will be used to explore De Groot’s vision of using computer software to design lean, mean, more potent vaccines, and then use a faster process for testing their effectiveness in humans. “The objective, actually, is to get some of this basic research into the clinic, to go from 20 years for making a vaccine to, perhaps, five,” said De Groot.

As technology improves, not only will we continue to see more vaccines that will prevent or treat diseases, but we may see more of them in record time.