Immunization Innovation: Advancements in Science and Policy Show Potential

To many in the United States, hand, foot and mouth disease (HFMD) is a common childhood viral illness that may include fever, rash on the hands and feet, and blisters inside the mouth. There is no vaccine, and it is not a reportable illness in the U.S. So why, then, has such a low-priority disease made headlines in early 2012 in four different U.S. states?

Between Nov. 7, 2011, and Feb. 29, 2012, the Centers for Disease Control and Prevention (CDC) received reports of atypical and more severe HFMD presentation in 63 cases across Alabama, California, Connecticut and Nevada. Subsequent virus strain sequencing in 24 of 34 patients tested showed coxsackievirus A6 (CVA6), an enterovirus associated with international outbreaks and more severe symptoms than the CVA16 strain typically seen in the U.S. Yet despite the genetic match to an international strain, epidemiological investigation was unable to confirm travel and directly link the cases to an imported source.¹

Where did it come from? In spite of the blip on the radar, HFMD remains a rare disease in the U.S., although it is endemic in parts of Southeast Asia, where approximately two million children are affected annually, and more virulent strains pose potentially debilitating and even fatal risks.² Dr. Dan Stinchcomb, co-founder and CEO of global vaccine development company Inviragen Inc., describes HFMD as an emerging disease. “One of the dangers is that it could be a problem here,” he tells the Coloradoan newspaper.³

And Dr. Stinchcomb would know. On March 12, Inviragen released results from its placebo-controlled, randomized Phase I trial of INV21, the company’s highly purified virus particle vaccine against enterovirus 71 (EV71), a virulent strain of HFMD endemic to East Asia. The study showed INV21 was safe and well-tolerated, and it significantly increased EV71 immune responses in all individuals receiving the vaccine. Inviragen will proceed with Phase II clinical testing shortly.²

HFMD represents one of many diseases with potential to benefit from recent breakthroughs in vaccine science. From enhancements in DNA research, to innovations in the manufacturing process, even the most routine diseases are meriting a second look. And partnerships between government, academia and industry are leading government officials to re-examine vaccine policies and recommendations as well, hoping to catch up with the science.

Advances in Global Health

With an increasingly mobile global population and renewed attention to the potential for global infectious disease pandemics, everyone stands to benefit from breakthroughs in the global health arena.

Cholera. PaxVax Corp. made news in March with the U.S. Food and Drug Administration’s (FDA) acceptance of its investigational new drug application for a cholera vaccine in the U.S. PXVX-0200, already approved and marketed in six other countries, is the only single-dose oral cholera vaccine worldwide, and provides immunity in as few as seven days, compared with other drugs that can take several weeks. PaxVax hopes to initiate Phase III trials shortly, and because the FDA classifies cholera as a “neglected tropical disease,” it believes they may qualify for a priority review voucher.⁴

Previously, there was a cholera vaccine manufactured and marketed by Wyeth Laboratories Inc. approved by the FDA in 1952. However, in September 2001, the FDA revoked the license for that cholera vaccine (a heat-phenol inactivated form) at the request of the manufacturer.

Malaria. While the malaria parasite’s crescent shape was first observed under a microscope in 1880, a viable vaccine has still remained elusive to researchers. But through modern high-end imaging techniques, University of Melbourne researchers believe they are one step closer to identifying a target for potential vaccine development. The team recently reported in the Journal Of Cell Science that, by using 3D Structured Illumination Microscopy and Cryo Electron Microscopy, they have discovered that malaria uses a “scaffold” of special proteins to form a banana shape before sexual reproduction. Researchers believe they may have found a new target in these “scaffold” proteins for a potential malaria vaccine.⁵

Vical Inc. recently announced its development of a potential DNA vaccine targeted at interrupting the malaria parasite life cycle as well. Initial test results published in the journal Vaccine describe the transmission-blocking DNA vaccine candidate as expressing the Plasmodium vivax malaria parasite protein Pvs230. Mosquitoes fed with malaria-infected human red blood cells incubated with serum from vaccinated mice successfully produced anti-Pvs230 antibodies and experienced a statistically reduced infection rate and number of parasites. Further study is expected.⁶

The Promise of DNA Vaccines

Many researchers are looking to DNA vaccines to improve immune responses to some of our most significant health challenges. DNA vaccines work by injecting genetically engineered DNA, which is absorbed into the body’s cells. The DNA contains coding for synthesizing a pathogen’s antigenic proteins, enabling the body’s cells to then create and display these proteins on their surface, alerting the immune system and triggering a response. Researchers believe this method holds potential for both chronic and infectious diseases, and various clinical trials have been performed or are ongoing. To improve immune response to DNA vaccines, many researchers also are examining new delivery technologies, formulations and prime-boost strategies.⁷ Although no DNA vaccines have yet achieved market licensure, research in the areas of influenza, HIV and even herpes simplex virus have recently made headlines.

Influenza. Influenza creates a unique challenge for scientists engaged in vaccine research. Because of influenza’s high propensity for mutation, each year the World Health Organization tries to predict the most likely dominate strains to come, and it directs seasonal vaccine manufacturers to focus their energies on those strains. Because these vaccines typically focus on the surface proteins, which vary across strains, vaccines must be altered and repeated each year to ensure maintained immunity.⁸ (MedImmune LLC just announced the FDA’s approval of its first quadrivalent seasonal influenza vaccine that contains four distinct vaccine strains. See story on page 50.) Research in the area of a universal influenza vaccine, which focuses on core proteins shared across influenza strains, also may benefit from a DNA vaccine approach.

Two recent Phase I clinical studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) report enhanced immune response to an H5N1 avian influenza vaccine in healthy adults first primed with a DNA vaccine expressing a gene for a key H5N1 protein. Some volunteers in the experiment receiving the prime-boost vaccine regimen also demonstrated production of broadly neutralizing antibodies (an early, yet significant finding for universal influenza vaccine research).⁹

HIV. Scientists at Emory University and GeoVax Labs Inc. have reported a successful vaccine regimen that includes a DNA priming vaccine, followed by an attenuated, poxvirus vaccine booster expressing HIV proteins, in the prevention of simian immunodeficiency virus (SIV) in nonhuman primates. (SIV is the nonhuman primate version of HIV.) The DNA prime vaccine co-expresses both HIV proteins and the normal immune response initiating protein GM-CSF (enhancing the ability to elicit SIV blocking antibodies before the virus enters cells). GeoVax reports that initial Phase I and IIa clinical trials of a similar first generation DNA vaccine (without the GM-CSF expression) showed “excellent” safety and reproducible vaccine responses in more than 400 HIV-negative people, helping to fast-track this second-generation DNA vaccine (expressing GM-CSF) to Phase IIb efficacy trials in people at high risk of HIV exposure. These trials are part of the National Institutes of Health HIV Vaccine Trials Network.¹⁰

Herpes simplex virus. At the 5th Vaccine and ISV Annual Global Congress in Seattle in October, DNA vaccine development company Coridon Pty Ltd announced it had successfully completed preclinical efficacy testing of its prototype herpes simplex virus 2 (HSV-2) vaccine, with results showing the vaccine was 100 percent effective in protection against HSV-2 infection in animals. Coridon plans to initiate preclinical safety studies shortly.¹¹

The Challenges of Cancer

One of the major challenges facing the immune system centers around identification of cancer cells themselves as harmful. Subsequently, the FDA has, to date, approved only one cancer treatment vaccine (for men with metastatic prostate cancer) and two types of cancer-preventing vaccines: a vaccine against hepatitis B virus (which can lead to liver cancer) and a vaccine against human papillomavirus (HPV) types 16 and 18 (which can lead to cervical, anal, vaginal and vulvar cancers).¹² What is exciting is that, in October 2011, the Advisory Committee on Immunization Practices (ACIP) voted to expand recommended routine use of the HPV vaccine Gardasil to males ages 9 to 26 years, ensuring equal protection across genders.¹³

Melanoma. Cancer vaccine efficacy faces limitations due to the low immunogenicity of cancer antigens. Researchers are, therefore, looking to strategies for enhancement. The Mayo Clinic in Rochester, Minn., recently reported success in training mouse immune systems to eradicate skin cancer through the use of a genetic combination of human melanoma cell DNA and vesicular stomatitis virus (VSV). By utilizing a highly immunogenic virus such as VSV (a cousin of the rabies virus), scientists were able to increase the visibility of the cancer antigens by the immune system, as well as improve immune response. “The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated,” explains Dr. Richard Vile. The Mayo Clinic hopes to initiate human clinical studies in the next two to three years.¹⁴

Breast cancer. At their April 2012 annual meeting, the American Association for Cancer Research (AACR) chose to highlight results from the Generex Biotechnology Corp.’s ongoing Phase II clinical trial of AE37, an immunotherapeutic vaccine to prevent relapse in patients with a history of breast cancer. The vaccine utilizes the company’s Ii-Key Hybrid technology platform to modify fragments of antigens and increase their immunogenicity. The resulting peptide vaccine contains a fragment of the HER2 protein (a highly potent cancer-expressing protein). Key findings from the clinical trials indicate that patients receiving AE37 develop an increase in circulating T cells in their blood and a reduction in T regulatory cells (known to hamper immune response). According to Dr. Elizabeth Mittendorf, principal investigator for the trial, these data suggest that patients receiving AE37 have a lower rate of relapse. “These studies help us to understand at a mechanistic level how the vaccine is working and on a more general level what hallmarks to look for in developing successful cancer immunotherapy,” she explains.¹⁵

Technological Advances Beyond the Needle

Some currently innovative approaches to vaccines lie in looking beyond the syringe itself.

Needle-free. Researchers at the University of Saskatchewan believe the first successful respiratory syncytial virus (RSV) vaccine may require going “needle-free.” RSV, a major cause of respiratory illness in young children, can lead to particularly bad sequelae in young infants, including pneumonia or bronchiolitis or, rarely, death. The challenge with any vaccine among the youngest infants is finding that delicate balance between inoculating a child early on before they are exposed to disease, and ensuring circulating maternal antibodies do not eliminate the vaccine before the child’s own immune system is able to develop an immune response. By delivering the RSV vaccine intranasally and avoiding the needle, the vaccine then initiates the immune response in the mucous membranes of the nose and lungs before maternal antibodies in the blood are able to inactivate the vaccine. Pan-Provincial Vaccine Enterprise Inc. is backing the research through Phase I clinical trials.¹⁶

Electrical currents. At the University of Oslo as well, researchers are finding that not all vaccine components must come from the needle. Their DNA vaccine studies do not require adjuvants to incite an immune response. Instead, they have developed a new technology that applies an electrical current to the injection site immediately after an injection of DNA code. It is this electrical pulse that results in skin cells absorbing the DNA and initiating the DNA-coded response — production of what they call Vaccibody molecules. This proprietary vaccine platform increases the antibody and T-cell responses, and could potentially be applied to a plethora of different diseases, as long as targeted antigens have a protein structure.¹⁷

Bar coding. Clinicians and patients at the point of care all will benefit from recent advancements in bar coding technology and updates to FDA requirements addressing vaccine labeling and documentation. In 2004, the FDA published guidance requiring industry to use linear bar coding containing National Drug Code (NDC) information on all vaccine products.¹⁸ But space constraints in the capacity of linear bar codes mean additional information such as expiration date and lot number cannot be included and must be recorded manually by the administering clinician into a patient record in order to meet requirements of the National Childhood Vaccine Injury Act of 1986. An updated August 2011 FDA guidance¹⁹ allows for manufacturers to request a linear bar code waiver in favor of alternative symbologies such as 2D bar codes, which can store significantly more data.

With a simple scan, clinicians can interface with electronic medical records and immunization registries, reducing staff time spent on documentation and improving data accuracy. Staff also will benefit from advancements in vaccine inventory reconciliation and improved patient safety. Accurate electronic tracking of vaccine lot numbers will help identify safety concerns with specific lots, allow for ease in patient identification in the case of supply recall, and significantly improve vaccine adverse events tracking.²⁰ The CDC is currently engaged in a 2D vaccine bar coding pilot project among 10 CDC immunization grantees and two vaccine manufacturers, Sanofi Pasteur (for use with Menactra and pediatric DT vaccines) and GlaxoSmithKline (for use with adult Havrix vaccine).²¹

Building a Future Together

The path to better public health is paved with research and technological achievements, but governments also hold a significant piece of the pie. Challenges experienced during delays of the 2009 H1N1 pandemic vaccine production have highlighted the need to move beyond traditional egg-based production technology, and to accelerate where possible the vaccine development, manufacturing and administration processes — a priority for the U.S. government as well. A 2011 report from the U.S. Government Accountability Office finds that from 2005 to March 2011, the Department of Health and Human Services (HHS) and the Department of Defense (DOD) have cumulatively awarded nearly $2.1 billion for the development of alternative vaccine technologies (such as cell-based and recombinant technologies and adjuvants research). The report also examines challenges to development and licensure identified by stakeholders, including high research and development costs and insufficient FDA guidance documents, and it outlines proactive HHS steps to address these issues.²²

Moving forward. HHS has made its plans for improvement known, and it is working to enhance the FDA’s staff expertise and to facilitate the review of licensing applications for new influenza vaccines using alternative technologies.²³ The FDA continues to engage stakeholders on multiple levels, particularly through its Vaccines and Related Biological Products Advisory Committee (VRBPAC).

TheVRBPAC meeting on February 29 of this year specifically addressed the challenges associated with licensure pathways of pandemic influenza vaccines, as well as the limitations in demonstrating pandemic vaccine effectiveness (a requirement for licensure). Quite simply, in order for a pandemic influenza vaccine to be licensed, the applicant must demonstrate data that support both safety and effectiveness. While it is possible to evaluate the safety and immunogenicity of a pandemic influenza vaccine candidate in a pre-pandemic period, it is not feasible for manufacturers to conduct clinical endpoint efficacy studies when the pandemic strain is not yet circulating. The committee seemed open to allowing inferred effectiveness of a pandemic influenza vaccine from the efficacy of a previously approved seasonal influenza vaccine made by the same manufacturer and process.²⁴ Stay tuned for further developments and guidance.

Yet It All Comes Back to Utilization

Of course, even when all the pieces come into play and modern medicine is able to tackle a significant health problem through achievements in immunization, sometimes the biggest challenge is making use of the resources we have — an issue the Indiana State Health Department knows all too well following a measles outbreak in February. The city of Indianapolis, host to the 2012 Super Bowl, made national headlines this year when it was discovered a highly infectious individual with measles had attended several activities at the nonticketed Super BowlVillage²⁵ (a three-block outdoor festival in downtown Indianapolis with estimated attendance in the hundreds of thousands).While the state was not able to directly link any of its subsequent 16 confirmed cases that month to exposure at the Super Bowl Village, the entire episode highlights the multiple opportunities for disease transmission in public settings, and the importance of maintaining high measles-mumps-rubella (MMR) vaccine coverage rates to protect U.S. citizens from measles importations and transmissions both domestically and abroad.

There is room for improvement: Data from the National Immunization Survey indicate that nearly one in 10 children has not received the MMR vaccine by age 19 months to 35 months. 26 (ACIP recommends the first MMR vaccination at 12 months.) Efficacy data show that more than 95 percent of people receiving even just the first MMR will develop immunity to all three diseases.²⁷

States are phasing in grade-specific school entry vaccination requirements, and recently the National Association of County and City Health Officials published a policy statement in support of eliminating personal belief exemptions for immunization requirements for childcare and school attendance (the brief did not address religious or medical exemptions).²⁸ On the whole, state and federal agencies seem poised and ready to engage in continued stakeholder dialogue and to accommodate advancements in research. Time will tell if immunization coverage rates and vaccine regulatory approval processes for vaccines will reap the benefits.