An Ebola Vaccine?

By Caroline Keroack, Jaya Rawla, Jillian Tozloski, Marie-Jacques Seignon

True as of October 22, 2014

An effective vaccine against Ebola will be essential for treatment and containment of the current epidemic in West Africa. Such a vaccine must be relatively safe, widely available, and elicit a strong immune response to be useful. Several Ebola vaccines have entered clinical trials with the goal of implementation in human populations by 2015 (Burton, 2014). To understand the implications of an Ebola vaccine, one must examine the basic biological workings of the vaccine, in addition to the social, economic, political, and logistical challenges associated with it.

A vaccine is a tool to train the immune system to fight off future infections by safely mimicking such infection (NIH, 2014). Vaccines can be made of attenuated live virus, dead virus, DNA, or short peptide sequences, which play the role of the antigen. Vaccines typically include an adjuvant in conjunction with an antigen to aid in detection by antigen presenting cells (APC), which then present the antigen on their cell surface. The displayed antigen is recognized by other immune cells known as helper T cells, which further activate killer T cells and B cells to destroy the infected APC. Other B and T cells form memory cells that will respond quickly the next time the same antigen is presented. These memory cells are what allow vaccines to be effective; any subsequent infection with the same antigen-producing agent will stimulate a fast immune response, essentially sparing the host from suffering from the effects of the pathogen (NIH, 2014; Rueckert, 2012).

Vaccine design relies on proper antigen selection. The antigen chosen cannot be a peptide or sequence that is rapidly changing, as the immune system would no longer be able to recognize it. The antigen must also be a portion of the pathogen that will be ‘seen’ by the immune system, thus surface proteins are usually used as antigens in vaccines. The challenge in selecting a proper antigen, or epitope, for an Ebola vaccine is that the current Ebola virus is rapidly mutating, and mutations do occur in the surface proteins (glycoproteins) that would be recognized by the immune system (Gire, 2014). Thus, a small peptide would not be an ideal antigen for an Ebola vaccine. To circumvent this problem, Ebola vaccines are being designed using the entire sequence of the glycoprotein gene. To accomplish this, the gene is incorporated into a vector, such as a virus or a plasmid, and delivered to the patient (Sullivan, 2000; Richardson, 2009). Adenovirus serotype 5 (Ad) has long been used in gene therapy and is known to elicit strong immune responses; thus, the virus acts as the adjuvant for the vaccine, and triggers a better immune response than naked plasmid DNA alone (Richardson, 2009; Tatsis, 2004). Once the glycoprotein gene is incorporated into the virus, it expresses the Ebola glycoprotein. This serves as the antigen, as the protein will be ‘visible’ to the immune system and allow the protective immune response and formation of memory cells to occur (Sullivan, 2000; Richardson, 2009). Hence, the design of an effective Ebola vaccine will not rely on a single epitope, but rather a full gene sequence to accommodate the high mutation rate seen in Ebola.

The most daunting challenge to implementing an effective vaccination program is successfully getting a vaccine through human trials. Several potential vaccines have completed animal testing with promising outcomes, but until recently nothing has undergone human trials (Galvani, 2014). As of late September 2014, phase 1 studies of an adenovirus vaccine (cAd3-ZEBOV) had started in both the United States and the United Kingdom. This vaccine uses a modified chimpanzee adenovirus that expresses glycoprotein from both the Sudan and Zaire strains of Ebola virus. A second set of trials has also started enrollment for testing of recombinant vesicular stomatitis virus vaccine (rVSV) that incorporates Zaire Ebola virus (ZEBOV) glycoprotein (Kanapathipillai, et al. 2014). Both of these vaccines are 100% effective in non-human primates and rVSV shows promise for protecting immunocompromised non-human primates (Geisbert, et al. 2008). Despite these successes, efficacy of these vaccines in humans remains unknown. The current vaccine prototypes incorporate the entire Ebola virus glycoprotein into their structures to accommodate the high mutation rate of the virus.

Several strains of Ebola are known to exist, so current vaccines must also attempt to provide blanket immunity against all strains. The cAd3 vaccine is being tested in monovalent and bivalent forms, meaning the vaccine can recognize 1 and 2 antigens respectively. The monovalent trials are based on the Zaire strain of the virus, while the bivalent trials will incorporate the Sudan strains in addition to the Zaire (Kanapathipillai, et al. 2014). The World Health Organization (WHO) is pushing for phase 1 trials to be completed quickly and the results be shared without prejudice so that phase 2 trials may begin in earnest. Ideally, WHO would like to proceed with phase 2 trials in two subdivisions. Phase 2a would be conducted in Africa, but in populations outside of the outbreak zone, while phase 2b would be conducted in exposed populations (Kanapathipillai, et al. 2014). However, given that phase 1 is still underway, discussion of phase 2 is still in the early planning stages. The earliest, optimistic estimate for vaccine in substantial quantity is spring 2015.

This significant delay shines a light on the other challenges to developing an effective vaccine, funding and time. Prototype vaccines for Ebola virus have been in early testing stages for years, but are usually stopped by a lack of funding (Reardon, 2014). In the past Ebola outbreaks have been short lived and have barely made a blip on the first world radar. Because of a lack of public interest, several teams of scientists researching potential vaccines lost their funding mid trial and were never able to successfully develop a human vaccine. Picking up where these scientists left off may seem like a head start, but in reality, time is still against effective treatment. Even if a safe and effective vaccine were developed, its deployment would face several challenges.

When a vaccine is developed, its implementation faces several economic, political, and social challenges. Economically, Guinea, Sierra Leone and Liberia have severely been affected by the Ebola epidemic, which, according to the World Bank, could cause a 30% to 57% decline in their growth rate (LA times). In addition, their current health care infrastructures and funding are relatively weak (The Economist). These economic challenges have lead to a growing inability for the citizens of these three countries to afford vaccination and have also increased their dependency on foreign aid. The latter being problematic as it is not a dependable source of income. For example, according to the UN, Afghanistan is falling $158 million short of its aid needs due to a relative lack of international attention (Al Jazeera). All three countries also have a relatively high degree of corruption. This could pose problems in actually getting vaccines to those who need to be immunized (Transparency International). Politically, both Liberia (2003) and Sierra Leone are recovering from civil war. A potential direction that the economic crises could take is political dissatisfaction and strife. Additionally Nigeria, where Ebola is present but contained, is also combating Boko Haram the radical militant group. Depending on a future development of events Nigeria’s attention could be further divided between combating the militant group and the viral epidemic. Effective vaccination measures would also face social challenges. Not only is the disease substantial stigmatized within civil society, especially given the economic slowdown that it has initiated, its virulence has also dissuaded international volunteers. While China and Cuba have sent close to 150 volunteers each (and planning to send more), a similar response has not been seen from the several countries in the global north (The Economist).

Anderson and May have underlined a strong relationship between the proportion of population to be vaccinated (p), the average age of vaccination (V), and the Ro of the infectious disease (Anderson, 1982). Looking at the current Ro (~2) and the average age of first infection (A=20-40 years old) for Ebola, a vaccination program that covers about 50% of the susceptible population at V < A, would greatly decrease the likelihood of another outbreak. Looking at the example of the measles outbreak from 1956 to 1970, which had A = 4 – 6 and V= 2.3, only 57% of the population was vaccinated and was able to bring down its Ro from 16 in 1956 to 12.8 in 1970. According to this model, higher proportion of vaccinated are needed in the case of infectious diseases with high Ro, high V and low vaccine efficacy (Anderson, 1982).

Promising strides towards the creation and implementation of an effective Ebola vaccine have been made. Significant challenges still obfuscate the clear and efficient production of such a vaccine. Social, economic, biological, and logistical obstacles render simple, traditional vaccine design ineffective. Thus exploring non-traditional vectors and public health tactics will be essential to the production and administration of any Ebola vaccine.

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