One can see Virology head of Institut Pasteur—how close
F. Tangy (shown)
Hum Vaccin Immunother. 2016 May; 12(5): 1102–1116.
Published online 2015 Dec 2. doi: 10.1080/21645515.2015.1122146
PMCID: PMC4963060
PMID: 26631840
Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination
Aline Baldo,a Evanthia Galanis,b Frédéric Tangy,c and Philippe Hermana
ABSTRACT
Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it attractive candidate vector to prevent infectious diseases. Attenuated MV have acquired the ability to use the complement regulator CD46 as a major receptor to mediate virus entry and intercellular fusion. Therefore, attenuated MV strains preferentially infect and destroy a wide variety of cancer cells making them also attractive oncolytic vectors. The use of recombinant MV vector has to comply with various regulatory requirements, particularly relating to the assessment of potential risks for human health and the environment. The present article highlights the main characteristics of MV and recombinant MV vectors used for vaccination and virotherapy and discusses these features from a biosafety point of view.
Introduction
Attenuated measles virus (MV) represents an attractive vector candidate for virotherapy and vaccination. This is due to several features including: (i) impressive track record of safety and efficacy in human population, (ii) lack of genomic integration in the host cells due to their cytoplasmic replication, (iii) high immunogenicity as vaccine, (iv) compared to other RNA viruses MV maintain high levels of genetic stability,1 (v) large foreign gene(s) insertion capacity (>6 kb)2 and (vi) selectivity to tumor cells in case of virotherapy applications….
These characteristics make measles vaccine attractive as a viral vector backbone for the development of recombinant vaccines against other viral infections such as human immunodeficiency virus (HIV), SARS coronavirus (SARS-CoV) and flavivirus infections.18-20 Nucleotide differences between the different attenuated vaccine strains used as vectors and MV-Edm are indicated in Table 1. … The choice of a strain for the design of the recombinant vector is based on the attenuation of the strain and its safe use as vaccine rather than nucleotide sequence analysis.
… Therefore, attenuated MV strains preferentially infect and destroy a wide variety of cancer cells making them attractive oncolytic vectors.24
Recombinant, attenuated MV strains are currently being tested in several phase I clinical trials as vaccine against HIV25 or chikungunya virus26 and as oncolytic vector in ovarian cancer, glioblastoma multiforme, multiple myeloma, head and neck cancer, and mesothelioma.24,27-29
The use of recombinant, genetically modified (GM) viral vectors for pre-clinical and clinical trials must comply with several European Union legislations including the legal provisions on biosafety aiming at protecting public health and the environment against potentially adverse effects of genetically modified organisms. Activities involving manipulation of GM viral vectors in contained conditions (e.g. laboratories, animal husbandries, production facilities, hospital rooms) may comply with Directive 2009/41/EC.30 Activities involving their deliberate release into the environment require that a case-by-case environmental risk assessment (ERA) should be carried out before release according the principles defined in annex II of Directive 2001/18/EC.31 The ERA is also part of the procedure for marketing authorization.32 The general steps underlying an ERA of viral vectors have been discussed in Baldo et al.33
This article focuses on biosafety issues in the European Union when performing clinical trials with recombinant attenuated MV vectors. The risk related to research and development activities and large scale production of these vectors are not developed in the present review….
Humans are the only known natural host for MV.23 Non-human primates can also be infected and are commonly used as model of infection. To date there is no known animal reservoir and no asymptomatic carrier state has been documented.
Measles (Rubeola) is one of the most contagious viral diseases known. Measles virus is efficiently transmitted by aerosols entering the respiratory tract or by direct contact with respiratory secretions.36,38 Its capacity of spreading is high, one person infected with MV can infect 15 to 20 others (R0 = 11–18),39 meaning that the interruption of endemic transmission in population requires that more than 95% of the population is immune.40 The infectious dose for wt MV is 0.2 units by intranasal spray.41
Measles virus has a cytoplasmic replication cycle eliminating the possibility of integration into the host cell DNA and then a possible insertional mutagenesis….
Attenuated measles virus generation
Attenuation of MV strains is the result of adaptation of the virus to growth conditions in non-permissive cell culture, especially avian cell lines.5 MV isolation and passages in CD150 negative cells such as human kidney cells and Vero cells may have selected the viruses capable of using CD46 as a receptor for viral entry into host cells.7,37,46 The use of CD46 by some MV strains may be considered as an in vitro adaptation rather than in vivo property of those strains.7 Likewise, the vaccine strains must have adapted to chicken embryo fibroblasts by using an unknown receptor present on them.7 CD46 is a complement regulatory protein that plays an important role in protecting autologous cells from complement attack….
Reverse genetics technology using a helper-cell-based rescue system2,51 allowed the rescue of replicating measles viruses from cloned DNA able to stably express heterologous antigens. This technology enables the rescue of clinically approved and genetically relevant measles vaccine strains.12,16,20,52  https://www.tandfonline.com/doi/full/10.1080/21645515.2015.1122146
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A toxicologist/pharmacologist named J.B. Fourtillan of France claimed more than a year ago publicly that Tangy made the Sars2 and managed to release it in Wuhan. Fourtillan who appears to be friends with Montagnier also cites various patents by F. Tangy that may be relevant in the case. It could be an inside leak from Institut Pasteur. Certainly worth looking into. -r.
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