The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials.

The devastating Ebola virus (EBOV) epidemic in West Africa in 2013-2016 accelerated the progress of several vaccines and antivirals through clinical trials, including the replication-competent vesicular stomatitis virus-based vaccine expressing the EBOV glycoprotein (VSV-EBOV). Extensive preclinical testing in animal models demonstrated the prophylactic and post-exposure efficacy of this vaccine, identified the mechanism of protection, and suggested it was safe for human use. Based on these data, VSV-EBOV was extensively tested in phase 1-3 clinical trials in North America, Europe and Africa. Although some side effects of vaccination were observed, these clinical trials showed that the VSV-EBOV was safe and immunogenic in humans. Moreover, the data supported the use of VSV-EBOV as an emergency vaccine in individuals at risk for Ebola virus disease. In this review, we summarize the results of the extensive preclinical and clinical testing of the VSV-EBOV vaccine.

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries.

INTRODUCTION: BCG remains the only vaccine against tuberculosis (TB) in use today and despite its impressive global coverage, the nature of BCG protection against the pulmonary forms of TB remains subject to ongoing debate. Because of the limitations of BCG, novel TB vaccine candidates have been developed and several have reached the clinical pipeline. One of these candidates is MTBVAC, the first and only TB vaccine in the clinical pipeline to date based on live-attenuated Mycobacterium tuberculosis that has successfully entered clinical evaluation, a historic milestone in human vaccinology. Areas covered: This review describes development of MTBVAC from discovery to clinical development in high burden TB-endemic countries. The preclinical experiments where MTBVAC has shown to confer improved safety and efficacy over BCG are presented and the clinical development plans for MTBVAC are revealed. The search of all supportive literature in this manuscript was carried out via Pubmed. Expert commentary: Small experimental medicine trials in humans and preclinical efficacy studies with a strong immunological component mimicking clinical trial design are considered essential by the scientific community to help identify reliable vaccine-specific correlates of protection in order to support and accelerate community-wide efficacy trials of new TB vaccines.

Vaccine platforms to control Lassa fever.

INTRODUCTION: Lassa virus (LASV), the most prominent human pathogen of the Arenaviridae, is transmitted to humans from infected rodents and can cause Lassa Fever (LF). The sizeable disease burden in West Africa, numerous imported LF cases worldwide, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. There are no licensed LASV vaccines and the antiviral treatment is limited to an off-label use of ribavirin that is only partially effective. AREAS COVERED: LASV vaccine development is hampered by high cost of biocontainment requirement, the absence of appropriate small animal models, genetic diversity of LASV species, and by high HIV-1 prevalence in LASV endemic areas. Over the past 15 years several vaccine platforms have been developed. Natural history of LASV and pathogenesis of the disease provide strong justification for replication-competent (RC) vaccine as one of the most feasible approaches to control LF. Development of LASV vaccine candidates based on reassortant, recombinant, and alphavirus replicon technologies is covered in this review. Expert commentary: Two lead RC vaccine candidates, reassortant ML29 and recombinant VSV/LASV, have been successfully tested in non-human primates and have been recommended by international vaccine experts for rapid clinical development. Both platforms have powerful molecular tools to further secure safety, improve immunogenicity, and cross-protection. These platforms are well positioned to design multivalent vaccines to protect against all LASV strains citculatrd in West Africa. The regulatory pathway of Candid #1, the first live-attenuated arenaviral vaccine against Argentine hemorrhagic, will be a reasonable guideline for LASV vaccine efficacy trials.

Novel strategies for development of hemorrhagic fever arenavirus live-attenuated vaccines.

INTRODUCTION: Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose significant public health problems in their endemic regions. Moreover, HF arenaviruses represent credible biodefense threats. There are not FDA-approved arenavirus vaccines and current anti-arenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. AREAS COVERED: Live-attenuated vaccines (LAV) represent the most feasible approach to control HF arenaviruses within their endemic regions. Different platforms, including recombinant viral vectors expressing LASV antigens, and the use of attenuated reassortant arenaviruses, have been used to develop LAV candidates against LASV with promising results in animal models of LASV infection, but none of them has entered a clinical trial. These vaccine efforts have been the subject of recent reviews and will not be examined in this review, which is focused on new avenues for the development of safe and effective LAV to combat HF arenaviruses. Expert commentary: The development of arenavirus reverse genetics has provided investigators with a novel powerful approach to manipulate the genomes of HF arenaviruses, which has opened new avenues for the rapid development of safe and effective LAV to combat these human pathogens.

Development of a recombinant, chimeric tetravalent dengue vaccine candidate.

Dengue is a significant threat to public health worldwide. Currently, there are no licensed vaccines available for dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent dengue vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naïve adults. TDV administration was generally well-tolerated independent of dose and route. The vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24-67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8(+) T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study.

Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward.

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.

Pandemic preparedness with live attenuated influenza vaccines based on A/Leningrad/134/17/57 master donor virus.

Continuously evolving avian influenza viruses pose a constant threat to the human public health. In response to this threat, a number of pandemic vaccine candidates have been prepared and evaluated in animal models and clinical trials. This review summarizes the data from the development and preclinical and clinical evaluation of pandemic live attenuated influenza vaccines (LAIV) based on Russian master donor virus A/Leningrad/134/17/57. LAIV candidates of H5N1, H5N2, H7N3, H1N1 and H2N2 subtypes were safe, immunogenic and protected animals from challenge with homologous and heterologous viruses. Clinical trials of the pandemic LAIVs demonstrated their safety and immunogenicity for healthy adult volunteers. The vaccine viruses were infectious, genetically stable and did not transmit to unvaccinated contacts. In addition, here we discuss criteria for the assessment of pandemic LAIV immunogenicity and efficacy necessary for their licensure.

[The protective activity of Yersinia pseudotuberculosis antigens]. / Protektivnaia aktivnost' antigenov Yersinia pseudotuberculosis.

Samples of Y.pseudotuberculosis (serovar I) antigens, represent a high-molecular lipopolysaccharide (LPS) fraction with a mol. wt. of 22.5 kD and fractions of outer membrane proteins isolated by the method of M. Osborn and R. Munson (1974), were tested in comparison with the activity with live cells of Y. pseudotuberculosis I attenuated mutant KV 9/2, having lost its Cad plasmid of virulence with a mol. wt. of 47 MD and carrying 2 attenuating markers: resistance to crystal violet and nalidixic acid. In experiments on guinea pigs pathomorphological studies demonstrated high protective activity of Y.pseudotuberculosis I attenuated mutant KV 9/2 and a pronounced protective effect achieved after the immunization of the animals with complex biopolymers, including a high-molecular LPS fraction and outer membrane proteins.

[A live vaccine against tick-borne encephalitis: the principles of selecting the vaccinal strains]. / Zivaia vaktsina protiv kleshchevogo éntsefalita: printsipy otbora vaktsinnykh shtammov.

The comparative, semiquantitative, pathomorphological study of the neurovirulence of clones of Elantsev virus and Langat virus TP-21 for intracerebrally infected monkeys has been carried out. The study has revealed that the viruses may be differentiated by their neurovirulence for primates according to the average statistical data on the degree of pathomorphological changes in the central nervous system, but not to maximum lesions in cerebral structures. The level of neurovirulence of yellow fever virus 17D was formerly considered to be the highest admissible limit of residual neurovirulence of encephalitogenic viruses (flaviviruses). According to our data, Elantsev virus, used for the immunization of humans and known to have caused some cases of encephalitis, is similar to yellow fever virus with respect to its neurovirulence for primates: therefore, a candidate strain intended for the preparation of tick-borne encephalitis (TBE) vaccine must be significantly less neurovirulent. The neurovirulence of clones isolated from Langat virus TP-21 has proved to be essentially lower than that of Elantsev virus clones. Langat virus TP-21 is a promising source of clones suitable for use as candidates for live TBE vaccine. Search for vaccine strains by testing their neurovirulence in experiments on several strains of mice and their hybrids, on hamsters and on immunosuppressed animals is methodologically groundless. The adequate evaluation of the level of residual neurovirulence of viruses to be used as candidates for live TBE vaccine can be made only on monkeys.

[The development of a technology for the production of live dried vaccines against avian pasteurellosis and swine erysipelas]. / Razrabotka tekhnologii proizvodstva zhivykh sukhikh vaktsin protiv pasterelleza ptits i rozhi svinei.

The technology of the production of dried live vaccine against Pasteurella infection of fowl from Pasteur's 2nd avirulent strain, strains AB and K, has been developed. This technology includes the process of batch cultivation of Pasteurella cells, controlled in such parameters as eH, pO2 and glucose concentration, in fermenters in optimized culture medium, based on Hottinger hydrolysate and fermentative casein-yeast hydrolysate, and preservation in improved saccharose-gelatin medium prepared in potassium sulfate buffer solution. The new technology makes it possible to increase the yield of preparations with stable biological activity 5- to 13-fold in comparison with the traditional technology. Furthermore, the technology of the production of live dried vaccine against swine erysipelas from Erysipelothrix insidiosa strain BP-2 has been developed. This technology is based on maintaining the optimum conditions of the batch cultivation of E. insidiosa in meat medium based on Hottinger hydrolysate and media obtained from hydrolysate of pancreatic fermentation products of microbial biomass; the preparation thus obtained is stabilized in peptone-saccharose-gelatin medium prepared in potassium phosphate buffer solution. This increases the yield of the vaccine 8-fold in comparison with the traditional technology, while ensuring the stability of bacteria after drying and during prolonged storage.

[Isolation of split and whole-virion tick-borne encephalitis vaccines in an experiment and the characteristics of their immunogenic and antigenic properties]. / Poluchenie rasshcheplennoi i tsel'novirionnoi vaktsin kleshchevogo éntsefalita v éksperimente i kharakteristika ikh immunogennykh i antigennykh svoistv.

The split preparation, obtained by the treatment of purified and concentrated tick-borne encephalitis virus with 0.5% Tween-80 and ether and inactivated with formalin at a minimal concentration of 1:10,000, did not contain the active virus. After the removal of the detergent, the preparation retained its antigenic and immunogenic properties.

[Experiments to produce an attenuated strain of the transmissible gastroenteritis virus and its use as a live vaccine]. / Opiti za polchavane na atenuiran shtam na virusa na transmisivniia gastroenterit i izpolzuvaneto mu kato zhiva vaksina.

Serial passages have been performed of a field virus of the transmissive gastroenteritis to obtain an attenuated strain adapted to a permanent cell line of pig kidney, "SPEV". The strain is innocuous for test animals, for pigs of all ages, and for swine during the entire period of pregnancy. It has proved genetically stable. The strain is immunogenic for swine and pigs both under laboratory and under field conditions (in new foci and on stationary farms) and can be used as a live vaccine against transmissive gastroenteritis, either untreated or in a freeze-dried state.

[Antigenic activity and the reactogenicity of a concentrated, purified, UV-inactivated cultured rabies vaccine]. / Antigennaia aktivnost' i reaktogennost' kontsentrirovannoi ochishchennoi inaktivirovannoi UF-luchami kul'tural'noi antirabicheskoi vaktsiny.

The results of the study of concentrated, purified, UV-inactivated cell-culture rabies vaccine, obtained from strain Vnukovo-22, passage 33-40, in the primary culture of Syrian hamster kidney cells, demonstrated the pronounced antigenic potency of this vaccine: when introduced intramuscularly in 3-4 injections at certain intervals, it induced the production of virus-neutralizing antibodies in high titers. In tests on volunteers the vaccine proved to be nonreactogenic.

[Comparative immunomorphological study of the immunogenic activity of dysentery vaccines produced by different methods]. / Sravnitel'noe immunomorfologicheskoe izuchenie immunogennoi aktivnosti dizenteriinykh vaktsin razlichnogo sposoba izgotovleniia.

The morphological study of the ophthalmic mucosa of guinea pigs immunized locally with different dysentery vaccines has demonstrated the advantages of live dysentery vaccine prepared from Shigella sonnei 6S over heated vaccine and Shigella antigen extracts. The protective properties of dysentery vaccines, their capacity for protecting the mucous membrane from the penetration and intracellular multiplication of shigellae correlates with the degree of the manifestation of vaccine-induced plasmatocellular reaction in the epithelial and subepithelial zones. The importance of the virulence of the strains used for the preparation of vaccines, as well as the method of their preparation, for the immunogenic potency of vaccines is shown.

[Concentrated adsorbed, cultured antirabies vaccine]. / Sorbirovannaia kontsentrirovannaia kul'tural'naia antirabicheskaia vaktsina.

In animal experiments the antigenic activity of adsorbed concentrated tissue-culture rabies vaccine was shown to be significantly higher in comparison with the nonadsorbed concentrated preparation when introduced in 2 intramuscular injections at an interval of 21 and 30 days, as well as in comparison with commercial tissue-culture vaccine when introduced subcutaneously in a 14-day course of daily injections.

[Production and study of the immunogenic properties of a bivalent inactivated vaccine against mucosal disease (bovine viral diarrhea and infectious rhinotracheitis)]. / Poluchavane i prouchvane imunogennite kachestva na bivalentna inaktivirana vaksina protiv mukozna bolest (virusna diariia i zarazen rinotrakheit po govedata).

Bivalent inactivated vaccine against mucous disease (MD) and infectious rhinotracheitis (IR) in cattle was produced from cell cultural MD and IR virus suspensions. The vaccine was concentrated on aluminium hydroxide, inactivated by ethanol and is without residual virus. Saponine in final 1:1500 dilution is added as supplementary adjuvant. Immunogeneity of the vaccine was tested on 10-month-old calves, which had shown full resistance against experimental infection with virulent strains of both viruses. Testing on calves for harmlessness by use of a five-fold higher vaccine dose indicated complete tolerance of the vaccine. The prophylactic effect of the vaccine applied in practical work to directly threatened with immediate MD and IR infection cows, including pregnant ones, consisted in reduced number of cases of abortion, of inborn malformations, in lower neonatal calf death-rate, etc. No disturbances were observed following two-fold vaccination of the animals, a fact proving its harmlessness. The positive results of the studied vaccine allow its further application in the combined prophylaxis of MD and IR in calf fattening and breeding complexes.