Fighting filoviruses

In this issue, Bausch and Geisbert present a review of the current situation concerning vaccines against Marburg virus. This deadly pathogen was identified in 1967 in Marburg, Germany, when infected green monkeys imported from Uganda transferred the virus to laboratory workers. Of the 32 infected people, seven died [1]. This was the first time a virus of the filovirus family was detected. Later, in 1976, Ebola virus was isolated during two outbreaks in southern Sudan and northern Democratic Republic of Congo (formerly Zaire). The case fatality rates in these two outbreaks were 50% in Sudan and approximately 80% in the Democratic Republic of Congo, indicating that two different strains of Ebola virus were causing these outbreaks. This was later confirmed by serological and molecular biological investigations [2,3].

Similar to many other highly pathogenic agents, filoviruses were tested for their potential to be used as biological weapons and are still on the list of agents that might be misused in biowarfare programs or bioterrorist attacks. Therefore, vaccine programs were started soon after the identification of filoviruses and after techniques had been developed to handle these agents safely in the laboratory. Early experiments revealed that the goal of developing vaccines against filoviruses was difficult to accomplish since inactivated virus preparations only confer partial protection to immunized monkeys [4]. Using molecular biological methods, it became possible to determine which viral proteins were involved in the development of a protective immune response and, finally, recombinant viruses were developed that appeared to be safe and conferred robust immunity against filoviruses in nonhuman primates (NHPs) [5–8]. This accomplishment is exciting and the work behind the success is immense since animal experiments with filoviruses are extremely dangerous laboratory tasks. Nevertheless, development of a vaccine candidate that is able to confer protection in a relevant animal model, such as NHPs, is the first step toward developing a safe vaccine for humans. What comes next?

First, it is necessary to ensure that the candidate vaccines are safe for humans. For DNA-based anti-Ebola virus vaccine candidates, safety testing has already begun [9] but testing of others is still required. The most promising candidates, recombinant adenoviruses and recombinant vesicular stomatitis virus, are expected to pass these tests. Then, for recombinant adenoviruses expressing filovirus proteins, one burning issue will be to overcome the problem of pre-existing immunity against the most frequently used vector platform, adenovirus type 5. Recombinant vesicular stomatitis viruses face the problem that their use is restricted to immunocompetent subjects. Nevertheless, both candidates are promising since they confer immunity to filoviruses after single-dose immunization. Moreover, recombinant vesicular stomatitis viruses expressing the surface protein of Marburg virus have the potential to be used as postexposure treatment against Marburg virus [10]. Research is needed to assess whether the development of strongly attenuated recombinant vesicular stomatitis viruses that simultaneously retain their protective ability is possible.

Since the appearance of filovirus infections is a rare event, even in endemic areas (<2000 known cases since identification of the first filovirus), it will be extremely difficult to prove the efficacy of a vaccine candidate against filoviruses. If efficacy tests turn out to be impossible, what are the alternatives? A possible method has been outlined by the US FDA regulations for drugs and biological products whose efficacy cannot be tested for ethical or practical reasons. This regulation states that, after the safety of a new drug or vaccine against a life-threatening disease is tested in human volunteers and the effectiveness of the vaccine has been demonstrated in relevant animal models, this vaccine can obtain approval for marketing if postmarketing studies are performed that demonstrate its efficacy.

The drawback of using a vaccine approved through this regulation is the potential reluctance of people at risk in remote African areas to accept vaccines that have only been tested in animals. In the past, international outbreak response teams were confronted with opposition from the local population repeatedly, which sometimes led to physical attacks against the teams [11]. Mistrust of foreigners that used unknown technology and who sometimes unintentionally ignored local cultural rites and beliefs made local people susceptible to propaganda. The rumors in Niger that poliovirus vaccines were prepared to sterilize African men and to spread HIV led to a general dismissal of polio vaccination and resulted in the spread of poliovirus to neighboring African and Near East countries [12]. It is, therefore, necessary to involve the local population carefully in vaccine campaigns against filoviruses. Accounting for fears and prejudices against vaccination that affect African populations and spread of infections to developed countries is a prerequisite for successful vaccination campaigns.

Importantly, most of the human outbreaks of filovirus hemorrhagic fever were initiated by hunters infected while handling infected monkeys [13,14]. Therefore, it might be beneficial to immunize NHPs in the endemic areas. This would help to protect endangered species and would also help to reduce the risk of filovirus outbreaks among humans.

To handle filovirus outbreaks effectively, we need to do more. The only way to contain filovirus outbreaks at present is to isolate patients in order to inhibit the spread of disease. To accomplish this task, the outbreak response team depends critically on the collaboration of people who might have become infected, for example, by caring for an infected relative. Since no treatment or vaccine is available currently, entering an isolation ward is extremely altruistic. Normally, people who enter the ward do not return alive and die without their relatives. Moreover, the burial rites often cannot be conducted as would be necessary to follow the cultural beliefs. Aggravating the reluctance of infected patients to agree to isolation is the fact that very often foreign doctors and nurses are involved in nursing patients in the isolation wards. Hidden behind face masks, goggles, overalls and gloves, the healthcare workers are not recognizable to the patients and appear like aliens. For all of these reasons, it becomes clear that we urgently need something that we can offer to patients in exchange for their compliance, such as a symptomatic therapy. This will turn out to be an enormous challenge. At present, we do not have drugs to treat filovirus infections. Moreover, specific and symptomatic therapy is complicated by the circumstances of the filovirus outbreaks (remote rural areas, often without safe water or electricity and danger to healthcare workers who provide help).

Is symptomatic therapy a promising avenue of therapy? The difference between the 25% case fatality rate during the initial Marburg virus outbreak in Europe in 1967 and the 80–90% mortality rate that accompanied the African outbreaks [15,16] suggests that intensive care might help to decrease the death toll of a filovirus outbreak. It is, therefore, necessary to consider whether, even in rural African settings, intensive care treatment is possible. This would require the close collaboration of all partners currently involved in outbreak response and the financial support of developed countries that appreciate that the treatment of hemorrhagic fever patients will also improve the treatment of patients in developed countries, where such diseases are rare. Increased professional and tourist travel activities will probably lead to an increase in the prevalence of such rare diseases in developed countries.

Finally, in addition to symptomatic treatment, it is necessary to investigate the possibility of specific treatment of filovirus hemorrhagic fever. One drug partially enhances the survival of NHPs after infection with Ebola virus; others might follow [17]. Approval of such drugs has been facilitated by the FDA and its European, Japanese, New Zealand and Australian counterparts. Special regulations have been developed for drugs against orphan diseases that are not of commercial interest. Nevertheless, it is necessary to find industrial partners that will add the development of drugs against filovirus hemorrhagic fever to their agenda.

The present review on Marburg virus vaccines shows the impressive progress that has been made over the last 5 years. However, this is not the point to stall further developments since immense efforts are still required. It is necessary to strengthen the collaboration among all potential partners, biosafety level 4 laboratories involved in filovirus research, private pharmaceutical companies, regulating agencies, outbreak response teams, wildlife specialists and politicians, to finally accomplish the goal of having a vaccine and treatment against filoviruses at hand.