March 26th, 2015
“We must accept the small suffering to prevent the big suffering”, Dirk de Wachter (Belgian psychiatrist) postulated in a documentary about happiness, providing the approach of this article about the battle against tick-borne encephalitis (TBE). Each year 10.000 – 12.000 cases of TBE are reported in Europe and the number of cases is increasing, indicated by the four-fold rise of TBE between 1974 and 2003 in the same continent (As reviewed by Suess, 2008). Methods to prevent tick bites are countless, however, TBE is still incurable: How can one combat TBE more effectively?
TBE is usually transmitted by ticks, which are eight-legged parasites that require blood from host animals for survival (Figure 1). If these ticks carry the TBE virus (TBEV), the virus is transmitted within the first minutes after the tick bite. Subsequently, TBEV causes TBE, which is an acute inflammation of the brain, causing swelling and bleeding in the grey matter. This infectious disease is characterized by nonspecific symptoms, like fever and fatigue, within the first ten days. Around three weeks after infection more severe symptoms appear, such as tremors, severe headaches and even altered consciousness (the “big suffering” according to De Wachter). Despite these alarming symptoms, early diagnosis is only possible if TBE is already suspected. Furthermore, specific treatment is still unavailable, illustrating the need for more effective treatment and prevention methods, with vaccination as an ideal candidate.
The invention of vaccination was a turning point in the war between microbes and humans (as reviewed by Pulendran and Ahmed, 2011). Due to more than 200 years of vaccinations, numerous diseases, such as tetanus and yellow fever (Massad et al., 2005), have been minimized. Most vaccinations consist of dilutions with infectious factors, which often cause short-term illness in the subject (De Wachter’s “small suffering”). Meanwhile, the immune system of the subject is getting prepared for the real infection. This is due to the elicited immune response against infectious factors and the subsequent formation of two major immune cells, namely (i) memory B cells, responsible for antibody responses, and/or (ii) memory T cells, responsible for cellular responses. Strikingly, when a new infection with these specific factors occurs, these memory cells rapidly start a strong immune response to defeat them at an early stage, preventing illness in the subject.
Vaccinations are roughly divided in two groups: (i) subunit vaccines, containing infectious factors and adjuvants (i.e. immune response supporting molecules), such as vaccines against tetanus and pneumococcus, and (ii) live attenuated vaccines, which are less infectious versions of the pathogen, like vaccines against yellow fever and chicken pox (as reviewed by Pulendran and Ahmed., 2011). Nowadays, live attenuated vaccines against viral infections, such as HIV and TBE, are the subject of intense investigation. Nevertheless, many of these vaccines are inconvenient, for they multiple doses and recurring boosters to maintain protected.
Recently, a convincing study by Rumantsjev and colleagues in PNAS describes the search for potent single-dose live attenuated vaccines against virus-caused TBE. The researchers constructed a number of virus-based vaccines based on two variables. First, these viral constructs contained either (i) all three structural proteins, like the infectious envelope E – called chimeras – (ii) or they lacked a functional capsid C gene (ΔC) – called single-cycle RepiVax-TBE viruses. The latter constructs have a disabled production of capsid C protein, causing replication-defective viruses, disabling their potential infectiousness. Second, they made several so-called viral backbones, consisting of seven nonstructural (NS) genes, which are more directly involved in viral replication (Figure 2). The effectiveness and safety of the TBE-vaccines are assessed after a single dose, unlike contemporary multiple dose vaccines against TBE.
Figure 2 (right) – Complete sets of genes (i.e. viral constructs), containing different backbones (WN, TBE, LGT, YF 17D or DEN2) in blue and different structural genes (with or without a functional capsid C gene) in green. If the capsid C gene is missing, the virus is unable to replicate.
Thereafter, the researchers selected the best single-shot viral vaccine by testing four major factors: (i) the stability of the viral construct, (ii) its neurovirulence, (iii) its neuroinvasiveness and (iv) its immunogenicity in mice. First, the stability of the virus is shown by the amount of mutations. Next, the more stable viruses were tested for neurovirulence and neuroinvasiveness, determining whether the viral vaccine itself causes a neurological disease in the lab animals or even mortality. Subsequently, the immunogenicity of the vaccines revealed their ability to cause an antibody response, which prepares the immune system to combat real infections. Thus, the researchers selected the most stable and immunogenic, yet least infectious and invasive variant. The best candidate was the RepliVax-TBE based on a West Nile virus backbone (RV-WN/TBE), which was therefore used for the follow-up experiments with Rhesus macaques.
Rhesus macaques were used as a model, because of their easy upkeep in captivity, their wide availability and their similarity to humans. In these primates, Rumantsjev and colleagues confirmed the high immunogenicity and safety, determined the best viral dose and revealed that the primates were protected against TBE after six months.
In summary, replication-defective RV-WN/TBE vaccines are effective and safe in two animal models, provoking a durable immune response. This achievement is observed after only a single dose, making it more convenient than current multiple-dose vaccines. Nevertheless, no cellular response is reported yet. Still, the vaccine has been successfully tested in primates, which are very similar to humans, which makes the step to clinical trials relatively small.
Notably, improvement of the RV-WN/TBE vaccine might be possible by combining it with a subunit vaccine, also known as the Multiple Antigen Presentation System (Zhang et al., 2013). This system combines the West Nile vaccine with infectious factor envelope E and an adjuvant. Finally, the most effective and safest TBE-vaccine is presumably a good model for future vaccines against HIV, another virus-based disease.
In conclusion, Rumantsjevs single-dose viral RV-WN/TBE vaccine is a promising solution for the battle against tick-borne encephalitis.