In today's Lancet
, Kathleen M Daddario-DiCaprio and colleagues1
show that treatment with a high dose of recombinant vesicular stomatitis virus containing Marburg virus surface glycoprotein is effective to prevent the deadly Marburg virus haemorrhagic fever. Surprisingly, prevention was achieved even if the vaccine was administered shortly after non-human primates had been infected with Marburg virus. Because no effective drugs against Marburg virus are currently available and symptomatic treatment of haemorrhagic fever is rarely effective, this is good news.
And this is the story behind Marburg virus. The highly pathogenic Marburg virus was first detected in 1967 in Germany, the first virus of the filovirus family.2
In 1976, detection of Ebola virus followed, which has caused unpredictable outbreaks of haemorrhagic fever in remote places in central Africa.3
Both viruses may be used as bioterrorism weapons. For several years, research on Marburg and Ebola viruses has been supported by anti-bioterrorism grants to find treatments, antivirals, and vaccines that cure the disease or protect against it.
Many attempts have been necessary to develop effective vaccine candidates to prevent filovirus-induced haemorrhagic fever. One approach was immunisation of guinea pigs with inactivated Ebola virus preparations, but the inactivated form provided incomplete protection giving a bad perspective on the feasibility of an Ebola virus vaccine.4
Then, recombinant filoviral proteins were used to immunise animals against Marburg or Ebola virus. The results suggested that both the cellular and the humoral immune responses could be activated and contribute to protection.5
Finally, a prime/boost strategy that combined recombinant DNA plasmids and recombinant adenoviruses, both expressing the surface protein of Ebola virus intracellularly, led to protection of non-human primates against Ebola virus haemorrhagic fever.7
To achieve the success reported in today's Lancet
, Daddario-DiCaprio and colleagues followed another approach. John Rose's group8
developed, in the mid-1990s, a system to rescue recombinant vesicular stomatitis virus from cDNA.9
Using this system, the gene encoding the surface protein of vesicular stomatitis virus was replaced by the gene encoding Marburg virus surface protein. The resulting recombinant virus was replication competent, slightly attenuated, and displayed the Marburg virus surface protein on the viral surface.10
Given to animals, this virus was well tolerated, led to robust cellular and humoral immune responses, and protection against Marburg virus infection.10
Recombinant viruses of this type have been used successfully to immunise animals against highly pathogenic agents, such as Ebola virus and Lassa virus,10
and were also used to protect monkeys from AIDS.8
The present report reveals that in the case of Marburg virus, the recombinant vesicular stomatitis virus system is even more powerful and could confer protection if administered shortly after infection with Marburg virus. This result is surprising and not fully understood. A specific cellular immune response against Marburg virus could not be detected in the treated monkeys, and mainly non-neutralising antibodies were detected after infection with Marburg virus and following immunisation with recombinant vesicular stomatitis virus. Possibly, competition between the overwhelming amount of vaccine virus particles and the relatively few infectious Marburg virus particles took place. Both bind to the same receptor leading to a situation in which infection is delayed to the extent that the animals' immune system could win the race. Probably, several mechanisms synergistically acted in favour of the host's immune system: the previously mentioned reduction of the infectious dose, in combination with a strong stimulation of the native immune response by recombinant vesicular stomatitis virus and production of specific antibodies against the Marburg virus surface protein. Clearly, more research is necessary to understand the molecular mechanisms leading to the postexposure prevention of Marburg virus haemorrhagic fever by the recombinant vaccine.
There is, as always with new treatments, a caveat to this approach: a fully replication competent recombinant virus can only be given to immune competent healthy persons. In a world with more and more people having defects in their immune response this may argue against this approach. Additionally, more safety tests with the recombinant virus are necessary.
What is the future of vaccines against Marburg virus and Ebola virus? Recombinant vesicular stomatitis virus containing the gene coding for the Marburg virus surface protein will probably not be developed to a commercial vaccine. A missing market is one reason. A difficulty to validate the effectiveness of the vaccines in humans because of the fortunately low number of naturally occurring Marburg virus or Ebola virus cases is another one. However, facing the enormous amount of money funnelled into investigation of agents that are supposed to have biowarfare potential, further development of currently available experimental vaccines against highly pathogenic viruses should be possible. At least, further development should allow treatment in emergency situations, such as a laboratory accident with filoviruses or protection of health-care workers in an outbreak of Marburg virus or Ebola virus.
I declare that I have no conflict of interest.