Despite tremendous successes in infectious disease prevention using standard approaches, effective vaccines have remained elusive for many serious infections. For decades, vaccines have relied on using weakened pathogens or their components to elicit immune responses that confer protection. This strategy has proven highly successful, significantly reducing the incidence of a number of diseases including polio, measles, mumps, and rubella. In fact, in the past 50 years, vaccination strategies have led to the eradication of smallpox, which is the only human disease considered to be successfully eradicated through vaccination. Despite numerous successes of currently employed vaccination technologies, it has proven difficult to develop efficacious vaccines for certain pathogens with high disease burden including HIV, RSV, and malaria. In addition, some currently available vaccines are considered suboptimal, such as the dengue fever vaccine Dengvaxia, and the seasonal influenza vaccines, which have to be reformulated every flu season. In the case of the influenza vaccine, yearly reformulations can lead to varying efficacies as the vaccine effectiveness is highly dependent on how well the vaccines match the prevalence of the circulating influenza strains. Here, I will highlight some of the key research data and trends presented at the 2017 Annual Conference for Vaccines Research held in Bethesda, MD from April 21-24, 2017 and touch upon innovative areas of vaccine technology.
DNA and RNA Vaccines
Emerging vaccine technologies are rapidly demonstrating efficacy for multiple diseases or conditions.
DNA and RNA vaccine technology stands out as an approach that may offer excellent vaccine efficacy and safety, and as platforms that expedite development compared to traditional vaccines. This emerging technology could allow for the rapid development of novel vaccines in response to unexpected rises in diseases incidences, such as Ebola or pandemic influenza outbreaks. In principle, DNA and RNA vaccines consist of either a plasmid or purified mRNA, respectively. Both of these approaches employ expression of an antigenic component of a pathogen or a neutralizing antibody with demonstrated efficacy in binding a specific pathogen. DNA- and RNA-based delivery of antigens have several distinct advantages over currently used technologies such as decreased development time and improved safety. This could result in rapid and widespread uptake, should they demonstrate excellent efficacy, safety, tolerability, and importantly, cost-effectiveness.
DNA and RNA vaccines can be developed rapidly in response to disease outbreaks such as Zika and Ebola. Abstracts S2-4 and Abstracts S3-1, S5-1, and S5-2
The Zika outbreak in 2015-2016 demonstrated that the Zika virus can be far more dangerous than previously expected, particularly for pregnant women in whom a significant number of pregnancies resulted in birth defects, most notably microcephaly. Importantly, it is unclear how prevalent Zika will be in future mosquito seasons, though a number of countries have implemented mosquito-control measures that appear to have decreased the number of cases of Zika infections. Nevertheless, Zika is still a serious concern, and a vaccine is still highly desirable for those living in and traveling to either Latin America or the southern United States and US territories. Shortly after uncovering the Zika outbreak, Inovio Pharmaceuticals in collaboration with GeneOne Life Science Inc. began developing GLS-5700, a DNA vaccine against the Zika virus. In primates, the DNA vaccine against Zika conferred 100% protection in challenge models, and the length of time from the initiation of the project to the beginning human trials was only 6.5 months, which is extremely rapid for any type of agent that could see use in humans. This vaccine was able to show near-100% efficacy in inducing immune responses in human subjects, showing that this technology is able to elicit immune responses in humans. A DNA vaccine is also in development for Ebola by Inovio Pharmaceuticals and has also demonstrated efficacy by conferring protection to 100% tested subjects in primate challenge studies. Like the Zika DNA vaccine, this vaccine also showed very high efficacy in inducing immune responses in humans. This is noteworthy as in May 2017, an Ebola outbreak was reported in the Democratic Republic of the Congo, and vaccine-based control measures may help curtail future outbreaks. In addition to Ebola and Zika, DNA vaccines may prove to be a highly valuable tool for rapidly responding to outbreaks of serious pathogens such as pandemic influenza, which can arise with little notice and cause significant morbidity and mortality. Further, because DNA vaccines can be modified and scaled up quickly, they would be useful in addressing mutations or genetic drifts that reduce the efficacy of currently available vaccines.
RNA vaccines have also shown promise and have easier administration than DNA vaccines. Abstract S5-2
RNA vaccines in principle work in a similar manner as DNA vaccines in that they both drive expression of an antigenic molecule. While RNA is inherently less stable than DNA, an HIV mRNA vaccine being developed by Acuitas Therapeutics is being packaged into lipid nanoparticles that can be administered via injection rather than electroporation, similar to currently available vaccines. RNA vaccines for HIV, influenza, and Zika have all shown complete or near-complete protection against challenges with these pathogens, with IgGs being induced 10 days after a single administration of the vaccine.
DNA and RNA vaccines could help reduce vaccine hesitancy. Particularly in developed countries, rates of patients declining to receive routine vaccinations has increased for a variety of reasons. Unsubstantiated concerns over safety are a key driver of vaccine hesitancy in the public, based largely on misinformation over components of vaccines being toxic, supposedly resulting in acute morbidity or developmental conditions such as autism. In addition, those who refuse vaccines often cite acquiring the illness they are being vaccinated against and sometimes being able to spread that illness to others, although neither of these circumstances have ever scientifically proven. As DNA and RNA vaccines would likely have a completely different formulation than current vaccines, lacking any agents which some claim are responsible for side effects (such as preservatives or adjuvants), and without administering the pathogen itself in any form, it would be difficult to argue that the aforementioned concerns are valid reasons not to receive a vaccine.
DNA and RNA vaccines hold promise, but cost-effectiveness and clinical validation have yet to be demonstrated. Abstracts S5-1 and S5-2
Both DNA and RNA vaccines are used to express a protein of interest. However, there is little data to suggest which of the two methods is the more safe and effective approach. DNA vaccines would be cheaper to manufacture than RNA vaccines, and have superior stability. However, RNA vaccines could be easier to administer and don’t carry the risk of integrating into the host genome, which can possibly lead to genetic mutations. The data demonstrated thus far for DNA vaccines is highly encouraging, despite the typical barriers that need to be overcome when introducing a new type of technology. One potential area that could slow uptake of DNA-based vaccines is the administration; currently marketed vaccines are extremely easy to administer via injection. However, some DNA vaccines will need to be administered via electroporation, which will need to be implemented in every locus of administration and will likely be associated with an increased cost for administration. Should widespread distribution of electroporators prove feasible, DNA vaccines may see strong uptake and revolutionize current immunization practices if they prove to be both safe and efficacious. Some DNA-vaccine electroporators are designed to be handheld devices, allowing any clinical setting where a DNA vaccine could be administered to have their own apparatus. Nevertheless, it is still unclear how much these devices will cost. Should they be expensive, route of administration could prove to be a barrier to uptake of electroporation-dependent vaccines.
Inovio Pharmaceuticals’ emerging therapeutic vaccine against HPV, VGX-3100, has demonstrated efficacy in regression of cervical cancer. Abstract S5-1
In addition to promising data for prophylaxis against the Ebola and Zika viruses, Inovio Pharmaceuticals’ therapeutic DNA vaccine against the oncogenic E6 and E7 proteins of HPV may help address HPV-associated cancers in patients who did not receive or did not respond to currently available HPV vaccines. Of patients who received the vaccine, 40% cleared their cancer or showed normal histology. While there are effective vaccines against HPV (Merck’s Gardasil/Gardasil 9 and GlaxoSmithKline’s Cervarix), uptake of these vaccines has been lower than expected due to a variety of reasons, such as lack of patient awareness of morbidities and mortalities associated with HPV, and the fact that the vaccines require multiple doses. Usually when there is an effective prophylactic vaccine for a pathogen, there is a reduced need for associated therapeutics. However, due to lower than anticipated uptake of HPV vaccines, HPV-associated diseases such as cervical, anal, and oral cancers will continue to be a concern and require treatment, driving commercial opportunity for any promising therapeutics in this space. As cervical cancer is largely caused by HPV infection and activity, both the prophylactic and therapeutic vaccines could significantly reduce HPV-associated cancer rates by reducing rates of infection and by helping treat HPV-associated lesions. Overall, this therapeutic vaccine will grow the market for agents used to address HPV, however should rates of vaccination for HPV prophylaxis significantly increase, there will be decreased need for any therapeutic options.
Genocea Biosciences has demonstrated positive Phase II data for its therapeutic vaccine against HSV-2, GEN-003. Abstract OA5-2
Unlike the Zika and Ebola DNA vaccines discussed above, Genocea Biosciences’ therapeutic vaccine is comprised of the HSV-2 antigens ICP4 and gD2 and a proprietary saponin-derived adjuvant. The vaccine demonstrated a 50% reduction in rates of HSV-2 shedding and of genital lesions, with the effects lasting for at least 12 months. Cellular and humoral immune responses to the vaccine antigens remained above baseline for 12 months. While a significant number of patients experienced adverse events following GEN-003 use such as myalgia (82-93%), fatigue (70-89%), and injection site tenderness/pain (89-98%) there were no serious adverse events and no patients discontinued treatment. These data are being used to optimize the Phase III trial design of GEN-003. While antiviral therapeutics are available for HSV-2, they only suppress the virus, and treatment is not always effective. Genocea Biosciences’ therapeutic vaccine could help improve treatment of HSV-2 while decreasing the treatment burden of having to take oral antiviral agents.
Vaccines Against Drugs of Addiction
Vaccines are capable of generating responses against molecules not associated with pathogens. Abstracts S3-1, S3-2, and S3-3
As the immune system is capable of mounting responses against carbohydrate, lipid, and protein components of pathogens, it is not surprising that other organic molecules have been shown to be antigenic. This lead to the concept of using the immune system to fight the effects of drugs of addiction, particular cocaine and heroin, via vaccination against the addictive agent. In theory, these vaccines would be used in patients with an addiction to help decrease the effects of the drug, in turn decreasing the ability of the narcotic to sustain the addiction. In animal models, a vaccine against heroin was able to decrease multiple biochemical and behavioral parameters associated with the effects of heroin and its addictive properties. In human trials, a vaccine against cocaine co-developed by Mass Biologics, Inc., Cleveland Biolabs Inc, the National Institute of Drug Abuse, and the Research Triangle Institute was able to prevent cocaine addicts from relapsing, and this effect was dependent on the serum levels of anti-cocaine antibodies, with higher levels of antibody correlating with fewer relapses. Aside from the well-noted hardships caused by addictive drugs and mortality associated with overdoses, combating and treating cases involving illicit drugs and opioids is profoundly expensive. In the United States alone, it is estimated that $37bn/year is spent on health care associated with these drugs, with an additional $270bn in costs related to crime and lost-work productivity. Should a vaccine against addictive drugs be successfully developed, they would ease a tremendous societal and financial burden caused by these agents.
Although a range of effective vaccines are currently available, tried and true approaches have been used for decades and are producing diminishing returns for new vaccines. New approaches to vaccine development are necessary to address pathogens for which established methods have failed to produce an effective vaccine, such as HIV. Additionally, more rapid techniques for vaccine development are needed to help combat the potential rapid emergence of pathogen for which no vaccine exists, such as Zika, or to combat new strains or variants of pathogens such as influenza. Highly encouraging data for emerging vaccine technologies are becoming increasingly common, however they are still early in development and questions linger on what impact these strategies will have in clinical practice.