A new approach to development of live vaccine against tick-borne encephalitis

Abstract

Tick-borne encephalitis (TBE) virus, like many other arboviruses, is very stable in genetic characteristics such as neurovirulence. Extreme difficulty has been encountered in efforts to reduce its pathogenicity artificially and therefore many attempts in the U.S.S.R. to attenuate the virus and to develop a live vaccine for mass vaccination have been unsuccessful. A killed formol-vaccine has therefore been widely used since 1939 (Smorodintsev, Levkovich & Dankovsky, 1940;Smorodintsev et al. 1941), at first made in mouse brain and later in tissue culture (Smorodintsev & Ilyenko, 1961). Unfortunately such vaccines have to be given annually and a more effective and convenient live vaccine would be a considerable advantage if safe and immunogenic vaccine strains could be found.Our first step in this direction was the study of the Langat (TP 21 strain) virus (Smith, 1956) because of its close antigenic relationship to TBE and absence of known natural disease caused by it in humans in Malaya. The mouse-adapted variant of Langat virus can be sharply differentiated from typical TBE virus on the basis of its inability to infect mice by intraperitoneal (IP) or subcutaneous (SC) inoculation and rhesus monkeys by intracerebral (IC) injection. The original Malayan strain grows poorly in chick embryo cells (CEC) at 40°C. and does not grow at 41-50 C. The original mouse brain virus contains a mixture of strains more or less pathogenic for mice, monkeys and man. The proportion of more virulent virus in the original mouse brain virus is very small but increases very sharply after five or more passages in CEC. Using terminal dilutions (which cause less than 50 % mortality in mice infected IC) thirty-eight pure clones of Langat virus including two virulent and thirty-six avirulent variants have been isolated from mouse-brain virus. These two main types of variant were genetically stable and were not changed in virulence by prolonged passage at 360 or 400 C. in tissue culture or by prolonged mouse-brain passage.

Attenuation of the Langat tick-borne flavivirus by chimerization with mosquito-borne flavivirus dengue type 4

“…The occurrence of vaccine-associated encephalitis, albeit at very low frequency (10 Ϫ4.3 ), which was observed during a large clinical trial of the attenuated LGT vaccine candidate (Yelantsev strain), supports this view (6,7). Ideally, live attenuated tick-borne flavivirus vaccines should be free of this very low level of virulence.…”

“…But before considering such LGT͞DEN4 chimeras for use in a novel live TBEV vaccine, it remains to be determined whether immunization of mice or nonhuman primates with LGT͞DEN4 chimeras also confers resistance to heterologous challenge with more virulent members of the TBE complex, such as the Far Eastern strains of TBEV. Earlier studies in animals and human volunteers suggest that this will be the case because immunization with attenuated LGT Tp21 or E5 induced a broad antibody response against various members of TBE complex (5,6,27,28).…”

“…Approximately 30 years ago Yelantsev virus (6), which subsequently was shown to be identical to wild-type LGT, strain TP21 (7), was evaluated in 649,479 individuals as a candidate live attenuated vaccine for prevention of tick-borne encephalitis. Studies were discontinued when it was discovered that vaccination was associated with a low frequency of encephalitis, approximately one case per 18,570 immunizations.…”

Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses

“…The introduction of mutations in prM or E or in the DEN4 NS1 gene of the chimera reduced neurovirulence for mice and also reduced replication in cell culture [154]. The chimera with or without attenuating mutations induced immunity and protected mice against lethal challenge with TBE [154,155]. Given the safety concerns around use of pathogenic viruses in constructing a live vaccine, attention refocused on alternative strategies.…”

“…The prototype LGT TP21 strain had actually been evaluated on its own in Russia for Jennerian vaccination against TBE [155], but had been associated with serious adverse events (vaccine-associated encephalitis) [156]. A derivative, the E5 strain, had been attenuated by serial passage in eggs to a point where it was less neurovirulent for mice than TBE virus and was considered a candidate vaccine strain [157].…”