Alphavirus-Based Vaccines

Abstract

Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against alphaviruses themselves. Recent progress in alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.

Vector-based genetically modified vaccines: Exploiting Jenner’s legacy

“…Total number of vaccines after deduplication 1146 Of which GM vaccines 762 Of which vector-based GM vaccines 226 [9,27,28,35,38,46] (continued on next page) Retroviruses -Long term gene expression -Generation of replication-competent virus -Infects dividing cells only [32] Lentivirus -Long term gene expression -Infects non-dividing and dividing cells -High immunogenicity -Generation of replication-competent virus -Potential for tumorigenesis [32,57] Bacteria Lactic Acid Bacteria (Lactococcus, streptococcus, pediococcus, leuconostoc, lactobacillus) -Autoimmune diseases -Naturally present in host -Much safer than traditional attenuated vaccines in children and immunocompromised people -History in food industry, recognised as safe -Probiotics, have health promoting properties -Capacity to survive the gastrointestinal tract -Mucosal administration could reduce traditional side effects -Limited knowledge available for use as vector vaccine compared to viral vectors [39,58] Listeria -Cancer -Induces both CD4+ and CD8+ T cell responses -Naturally present in host -Pre-existing immunity can lead to stronger immune response -Much safer than traditional attenuated vaccines in children and immunocompromised people -Induce robust T-cell immune response -Can invade a variety of cells, including antigen presenting cells -Can reside in the cytoplasm -Limited knowledge available for use as vector vaccine compared to viral vectors [39,59] (continued on next page) Salmonella -Salmonellosis (in animals) -Typhoid fever -HIV infection -Naturally present in host -Pre-existing immunity can lead to stronger immune response -Much safer than traditional attenuated vaccines in children and immunocompromised people -Induces robust T-cell immune response -Induces both humoral and cellular immune responses -Can induce both mucosal and systemic immunity -Able to carry large DNA inserts -Pre-existing immunity could still be a limiting factor -Limited knowledge available for use as vector vaccine [9,39,60] Various search terms were often found in literature to define GM vaccines, nevertheless these terms were all used in an inconsistent manner. The definition of GM vaccines was narrowed down by delineation of search terms found in CPC codes and literature.…”

“…Altenburg et al [48] Nébié et al [44] Arroyo et al [34] Nieto and Salvetti [30] Babu Appaiahgari and Vrati [33] Ondondo [52] Banchereau and Steinman [36] Pandey et al [27] Bermúdez-Humarán et al [58] Paris et al [43] Bråve et al [28] Ploquin et al [31] Chin'ombe et al [60] Rimmelzwaan and Sutter [55] Choi and Chang [35] Robertson [51] Cottingham et al [56] Rollier et al [11] Croyle et al [41] Saxena et al [39] Dicks et al [40] Smith Tatsis and Ertl [37] Ewer et al [45] Tripp and Tompkins [47] Gómez et al [49] Ulmer et al [3] Hessel et al [54] Ura et al [32] Kreijtz et al [26] Verheust et al [53] Lundstrom [46] Weaver and Barry [42] Mooney and Tompkins [38] Williams et al [29] Myhr et al [50] Youngjoo et al (2013) For the clinical trials analysis, a similar procedure was applied. Instead of searching for CPC codes, data on the technology class of the vaccine was extracted from the previously generated clinical trial database by searching the variable ''Expression System".…”

Replicon RNA Viral Vectors as Vaccines

“…The DNA layered system applies plasmids carrying alternatively the nonstructural genes or the full-length genome and the GoI for direct immunization with DNA. All vector system approaches described above have proven efficient in immunization studies as presented below [4]. …”

“…Alphavirus vectors have been applied in many studies on cancer vaccines [4,8]. In principle, tumor-associated antigens (TAAs), immunomodulating cytokines and combination therapies of TAAs and cytokines, TAAs and antibodies, cytokines and antibodies and even microRNAs (miRNAs) have been evaluated.…”

“…Recently, the approach of vaccination with recombinantly expressed antigens and immunogens from viral and non-viral delivery systems has been introduced to the repertoire [2,3]. In this context, immunization with surface proteins and antigens has elicited strong humoral and cellular immune responses and vaccinated animals showed protection against challenges with lethal doses of infectious agents or tumor cells [4]. …”