When recent global epidemics have occurred, there has often been a call to rapidly develop a vaccine intended to protect those as yet uninfected. Often this process has been much more complicated than is realised, however. The recent development of a dengue vaccine is a case in point.
Following vaccination, against dengue for example, our immune systems are introduced to certain aspects of the virus, so that our white cells capable of recognising dengue can be increased. We are born with a collection of white cells capable of responding to infections to an enormous range of viruses: one white cell can recognise one particular viral sequence. If that one white cell meets its intended virus, it is ‘triggered’ to produce many more copies with the same ability to respond to the same virus – appropriately these are called clones. With the increased number of specific white cells to a particular virus comes an increased ability to kill the virus – which is the purpose of our immune system. Following vaccination then, the body is artificially introduced to a harmless version of the virus in order to build-up the pool of white cells able to respond to the virus, should the individual meet it.
Such a vaccine has now been established for the mosquito-borne illness, dengue fever. As dengue is a large global health concern, infecting around 50 million to 100 million people each year, and killing around 20,000, why have we not heard more about this?
Firstly, the initial release of the vaccine has only been to a few countries in South America and the Far East. Secondly, the WHO has expressed some reservations about its general usage in all populations. In their excellent position paper, the WHO has recommended that the vaccine is only considered in countries where the background exposure to dengue is at least 70%. This is because if the vaccine is used more widely there are some fears, although contested, that the vaccine might actually make subsequent infections with dengue (in some people) much worse.
The vast majority of patients infected with the dengue virus develop symptoms akin to a nasty flu: they suffer from malaise and headaches, joint pains and weakness. In a fraction of cases, however, patients can produce a serious complication known as dengue haemorrhagic fever. This complication is characterised by uncontrolled bleeding, in association with multi-organ failure, often resulting in death. It has been realised for some time that this life-threatening condition is much more likely to result when the patient has already been infected with dengue in the past.
The situation is a little more complicated. In fact, there are 4 distinct dengue viruses, and the haemorrhagic fever has been particularly noted to occur when a patient is first infected with one type of dengue virus but subsequently infected with another type of dengue. The reasons for this are not completely understood but a prominent theory is that the weak immune response developed following the first infection with dengue, can actually make the subsequent infection worse by a process called antibody dependent enhancement. During this process our antibodies actually facilitate the dengue virus entering certain of our white cells, allowing the virus to thrive and increase in number.
There has therefore been a fear that following vaccination of a patient who has never caught dengue in the past (for example children, or travellers and expats), the partial immunity developed from the vaccination may make their dengue fever much worse when they later become infected with dengue for real.
Although it is early days in the experience of the vaccine, a paper in the New England Journal of Medicine points out that around 30,000 children have now been immunised with the dengue vaccination and no increased incidence of the hospitalisations attributable to antibody dependent enhancement has been seen. This may bode well for travellers and expats in tropical and sub-tropical countries who are interested in getting vaccinated in the future. At present, however, it is wise to follow the cautionary approach from the WHO: wait for more to be known and to continue with the tried-and-tested mosquito prevention strategies. People are still strongly advised to use DEET containing sprays, wear appropriate clothes, and make use of air-conditioning and bed-nets if possible. Even if vaccinated, such precautions will still be necessary as the dengue vaccine offers only limited protection (about 60%), is unlikely to protect against Zika (although there is a large degree of similarity between dengue and Zika), and will certainly not protect against other mosquito-borne illness, such as yellow fever and malaria.
The recent outbreak of Ebola in West Africa has increased our knowledge of this previously little understood, devastating infection. We already realised that like dengue fever, Ebola can cause multi-organ failure and haemorrhage, but Ebola causes this severe disease much more frequently, resulting in death in 50%-70% of cases, depending on the extent of local healthcare provision. What has only been clear following the West African outbreak, however, are the ramifications of what happens to those who survive the infection. A post-Ebola syndrome has now been identified that features persistent muscle and joint pain, headache and eye problems. This was well demonstrated by the British Ebola nurse Pauline Cafferkey, who had several hospitalisations for ongoing concerns following her initial infection with Ebola in Sierra Leone.
A recent addition to our knowledge of the transmission of the virus has been the discovery of persistent carriage of Ebola in the seminal tract, allowing for sexual transmission many months after recovering from the infection. A study in Monrovia has followed 149 men who had recovered from Ebola: 13 such men were initially found to have evidence of Ebola in their semen. At the end of the study it was shown that 11 of the 13, still showed signs of infected semen two years following their initial infection with Ebola. Whilst it is unclear whether a positive Ebola test means the same as being capable of infecting another person with Ebola, this study does shed light on the possible causes for the several small recurrences that have occurred in West Africa since the main outbreak finished.
The reason that Ebola can persist in the semen is that a few parts of the body are shielded from our immune system, preventing the immune cells from clearing viruses in those sites – even when effective immunity to a virus has been gained for the rest of the body. The testes, as well as the brain and eyes, have been well known to harbour viruses long after the viruses have been cleared elsewhere. Somewhat perversely, these sites are termed immunologically privileged. In an analogous fashion to the studies that have shown that the Zika virus can be harboured in the testes for many months following infection, Ebola has now been shown to be capable of the same thing – allowing for small outbreaks to crop up from time to time. As long as the increased vigilance for Ebola continues, these outbreaks should be quashed at an early stage, as has been the case over recent months.
Written by Dr. Simon Worrell, Head of Medical Communications.