Update on Conventional vs. DNA Vaccines

WIDESPREAD IMMUNIZATION is perhaps the greatest technological achievement of the 20th century. More than powered flight, telecommunications, the adoption of electrical power grids or the computer revolution, the use of vaccines to largely eradicate dozens of diseases that formerly ravaged cities and nations improved more human lives than any other single innovation — perhaps even more than all the above developments combined.

Smallpox, yellow fever, pertussis, measles, polio, cholera, typhoid fever, encephalitis and meningitis are diseases that once caused epidemics that today are nearly unknown in developed nations due to the introduction of vaccines (although measles has shown a resurgence in outbreaks largely due to the antivaccine movement). Individuals are also now routinely inoculated against less deadly but still costly diseases such as chickenpox and mumps.

Somewhat amazingly, the basic medical underpinnings of vaccines haven’t changed since the first vaccine was discovered in 1796, when Edward Jenner exposed a young boy to deadly cowpox, and then demonstrated the boy had developed an immunity to the far more deadlier smallpox. Since then, every developed vaccine has stimulated the body to produce protective antibodies by introducing a dead virus or bacteria, a weakened (attenuated) virus or bacteria, or a closely related but less dangerous virus or bacteria (e.g., cowpox to provide protection against smallpox).

New technology, though, promises a more fine-tuned approach — one that is more consistent in provoking immunity while also potentially less expensive to produce and easier to speed production in case of a future outbreak.¹ This new “DNA vaccine” technology has also shown some early promise in helping the body fight some cancers. To date, however, the only DNA vaccine approved is a veterinary vaccine for West Nile virus in horses.² No human vaccines are yet approved for use.

The Development of Vaccines

It was known even in antiquity that survivors of smallpox gained immunity to further infections of the disease. The first inoculations involved swabbing the tip of a lancet on a pustule of an infected patient and then piercing the skin of an uninfected person. It was highly unsanitary, and it often resulted in secondary infections such as tuberculosis or syphilis. But it also worked, with a much lower fatality rate than a regular case of smallpox, and those who survived the inoculation didn’t have to fear contracting it again.

When the wife of the British ambassador to Turkey saw how the Turks inoculated their children by this method in 1718, she had her own children treated, and she demanded the British government adopt a similar program. This practice, known as variolation, remained the standard preventive for smallpox until Edward Jenner’s use of cowpox six decades later.

While Jenner was far from the first to realize exposure to cowpox granted immunity to smallpox (it was common knowledge in dairy-producing regions of Europe), he was the first to devote himself to promoting the use of cowpox as a widespread vaccine to prevent smallpox. His efforts resulted not only in formal vaccination programs in Britain and Europe, but in the United States as well, where President Thomas Jefferson was persuaded by one of Jenner’s associates to start the National Vaccine Institute after his own family and neighbors were successfully vaccinated.³

How Traditional Vaccines Work

While doctors knew an initial infection generally granted immunity to further infections of the same disease (not just for smallpox, but also chickenpox, mumps and other common diseases), they didn’t understand why. It was only in the 20th century when physicians and researchers discovered how vaccines stimulated immunity in the body, and those discoveries led to new ways of inoculating against infectious diseases.

When a hostile microbe (virus, bacteria or fungus) invades the body, it is met by specialized white blood cells called macrophages that will attack any cell that doesn’t have the same surface markers as all the other cells produced by the body. But, after destroying the invading microbe, the macrophage preserves a portion of its membrane and takes it to the lymph nodes, where the body begins churning out millions of immune cells to go look for that specific pattern of marker (also known as an antigen).⁴ These antibodies have an interlocking molecular pattern on their surface, so when they find another microbe with the antigen that matches, they can latch on to it and prevent it from reproducing.

During an initial infection for a specific disease, it can take the body a few days to ramp up its defenses and kill off the invaders. But, it keeps a supply of those specific antibodies on hand, and if a patient again comes into contact with that same bacteria or virus (or one with very similar antigens), it will overwhelm the invader before it has a chance to multiply.

Vaccines harness the body’s own self-defense mechanisms to mimic that initial invasion and ramp up production of the antibodies to fight off that species of infection so when the patient is exposed, the body is ready to fight.⁴ Most vaccines do this by introducing a weakened strain of the microbe in question, or by using dead microbes. Others such as the early smallpox vaccine use a closely related microbe that fools the body. Some vaccines use live-attenuated viruses such as those for chickenpox, yellow fever and rotavirus.⁵ With live-attenuated vaccines, a patient often gets a mild case of the disease, but acquires the ability to fight off future infections. Other vaccines such as those for influenza (flu), hepatitis A and polio use a dead version of the virus. With these, there is no risk the patient will acquire an active infection, yet the body still produces the antibodies that will identify these microbes if they enter the body.

More recently, researchers have discovered they can stimulate the body’s immune system with only a portion of the microbe — a specific protein or its capsid. These are safer for patients who have a compromised immune system, but often need periodic boosters to maintain immunity. Examples of these subunit, polysaccharide and conjugate vaccines are those for Haemophilus influenza type b (Hib), hepatitis B, meningitis, pertussis and human papillomavirus (HPV).⁵

How DNA Vaccines Work

The promising new approach of DNA vaccine involves injecting a small strand of bioengineered DNA that has been crafted into a circle, known as a plasmid, into a patient by one of several means. The cells that absorb this plasmid then follow the instructions of the DNA it contains and begin manufacturing that antigen and incorporating it into their cellular membrane, stimulating the body to produce antibodies to fight it. Researchers emphasize the plasmid does not enter the cell’s nucleus or mingle with the cell’s own DNA; instead, the DNA plasmid remains in the cell’s cytoplasm.⁶

DNA vaccine technology helps to accelerate the immune system’s ability to identify a hostile antigen and respond to it. However, early tests in the 1990s of this technology found too few cells absorbed the plasmids to sufficiently stimulate an immune response. Therefore, subsequent research has focused on new methods of getting the plasmids into cells in the body. 6 Some possible delivery systems being studied include encasing the plasmid in a live harmless bacterium and introducing it into the body, or using nanoparticles of a specific chemical makeup to increase the odds of them being absorbed into a cell.⁷

Researchers point out that once a plasmid has been created for one disease, repurposing it for another simply requires swapping out the genes that code the antigens.⁸ In theory, for instance, this would allow effective vaccines to be produced for each seasonal strain of the flu. Rather than the current practice of trying to guess which flu strains will be most predominant and creating a vaccine months ahead of time, pharmaceutical companies could wait for the first outbreaks and then quickly manufacture a vaccine in a matter of weeks.

While DNA vaccine technology has not yet been approved for use in humans, clinical trials are under way. Studies on mice have found DNA vaccines are highly effective, but that success has not translated to larger mammals — mainly because of the failure of enough cells to absorb the DNA plasmids and construct the antigens.

DNA vs. Recombinant Vaccines

What can get a bit confusing is that vaccines using recombinant DNA have been on the market. But, recombinant DNA vaccines are a similar but distinct process. They are manufactured by introducing the DNA strand for creating an antigen into a bacterial or other nonhuman cell, allowing it to create the antigens, and then harvesting the antigens to use in the vaccine.⁹ In other cases, the genetically altered bacteria with the antigen on its outer membrane can serve as the vaccine, thus mimicking the infectious microbe and provoking the body’s immune system to produce antibodies.¹⁰

Other Uses for the Technology

In addition to recoding the body to fight a specific infectious agent, there is ongoing research investigating whether DNA vaccine technology might be used to help the body fight cancer. Since cancer cells mutate quickly, and often feature an antigen different from the body’s own cellular membrane markers, it may be possible to use DNA vaccine technology to stimulate the body’s immune system to more efficiently target and destroy malignant cells.¹¹

Other researchers are investigating whether DNA vaccines can help desensitize the body to allergens. These use a dendritic cell-based approach to enhance immunogenicity.¹²

Risk Factors with DNA Vaccines

There are some concerns associated with DNA vaccines. Because little is known about the long-term implications of introducing altered genetic material into human cells, scientists are warning there may be unanticipated risks. These include 1) insertional mutagenesis, in which the DNA of a treated cell in a patient is permanently altered by the vaccine, 2) accidentally altering the DNA of a cell that could conceivably make it malignant and 3) whether the presence of these antigens in the body might introduce tolerance instead of immunity over a long time period.

Yet, researchers are optimistic these side effects will not manifest. “DNA has an extraordinary safety profile so far in the clinic,” said David Weiner, PhD, executive vice president and director of the University of Pennsylvania Wistar Institute’s Vaccine and Immunotherapy Center. “I think we are well over 35,000 people without a single major adverse event related to product.” According to him, there has been no evidence DNA plasmids are accidentally merging with the cells’ own genome in the nucleus, an obvious concern.⁸

Ongoing Research

As of this writing, there are more than 500 DNA vaccines studies listed on clinicaltrials.gov. Among them are studies investigating the effectiveness and safety of DNA vaccines targeting hepatitis B, melanoma, genital herpes, dengue fever, several strains of flu, pancreatic cancer, prostate cancer, hantavirus, metastatic breast cancer, HIV, malaria, HPV and dozens more. And, most of these diseases have several ongoing studies that take different approaches to deliver DNA into the cells.

One such approach is the use of electroporation, which introduces a pulse of electricity to momentarily open the pores of cellular membranes to allow the DNA plasmid to be absorbed. According to researchers, this process looks promising for an efficient delivery mechanism to induce the DNA plasmids to be absorbed into the body’s cells to begin producing the antigens that will stimulate the body’s immune response.¹³ Indeed, this delivery method is part of nearly every disease study looking at vaccination with DNA technology.

Political Considerations

Given the small but well-organized and passionate opposition to mandatory inoculations with existing technology, it is difficult to imagine DNA vaccines won’t be met with resistance. Lingering suspicions arising from a long-discredited (and withdrawn) 1998 article that purported to link vaccines with a rise in the number of children diagnosed with autism continues to fuel much of the opposition. Whether an entirely new technology of vaccines will help to alleviate that political pushback remains to be seen, but it is something policymakers and public health officials will have to factor into their long-term plans.

The Future

While there is much excitement about DNA vaccines, and several clinical trials are showing promise, the technology has existed for a quarter century, and we’ve yet to see an approved product for human use. So, while the promise is very real, there are considerable technical challenges facing researchers and clinicians. It is possible electroporation will prove to be the magic bullet for an effective delivery system, unlocking a technological logjam in the very near future.

For now, the promise of DNA vaccines is balanced by a tremendous amount that remains unknown. Physicians should continue to stay current on developments, as it seems likely DNA vaccines will at some point be another tool available to help prevent both infectious diseases and possibly treat cancer as well.