Fighting Fire with Fire: Immunogenicity of Viral Vectored Vaccines against COVID-19.

The persistent expansion of the coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the rapid development of safe and effective countermeasures to reduce transmission, morbidity, and mortality. Several highly efficacious vaccines are actively being deployed around the globe to expedite mass vaccination and control of COVID-19. Notably, viral vectored vaccines (VVVs) are among the first to be approved for global distribution and use. In this review, we examine the humoral, cellular, and innate immune responses elicited by viral vectors, and the immune correlates of protection against COVID-19 in preclinical and clinical studies. We also discuss the durability and breadth of immune response induced by VVVs and boosters. Finally, we present challenges associated with VVVs and offer solutions for overcoming certain limitations of current vaccine regimens. Collectively, this review provides the rationale for expanding the portfolio of VVVs against SARS-CoV-2.

Comparison of Marek's Disease Virus Challenge Strains and Bird Types for Vaccine Licensing.

Marek's disease virus (MDV) is an important poultry pathogen that is controlled through widespread vaccination with avirulent and attenuated strains. However, continued evolution of field viruses to higher virulence has required ongoing improvement of available vaccine strains, and these vaccine strains offer an attractive platform for designing recombinant vector vaccines with cross-protection against MDV and additional pathogens. Recent reports of failures in vaccine licensing trials of positive controls to reach appropriately high levels of Marek's disease incidence prompted us to evaluate possible combinations of outbred specific-pathogen-free layer lines and alternative virulent challenge strains that could provide more consistent models for serotype 3 vectored vaccine development. Choice of layer line and virulent MDV challenge strain each contributed to the ability of a challenge model to reach 80% virulence in unvaccinated positive control groups in the majority of trials, without overwhelming serotype 3 vectored vaccine protection in vaccinated groups. Conversely, reducing challenge virus dose by a factor of four, or vaccine dose by half, had no consistent effect across these models. Although MDV strain 617A had the most potential as an alternative to strains that are currently approved for licensing trials, no combination of layer line and challenge virus consistently met the goals for a successful challenge model in all study replicates, indicating that high variability is an inherent difficulty in MDV challenge studies, at least when outbred birds are used.

Artículo regular­Comparación de las cepas de desafío del virus de la enfermedad de Marek y los tipos de aves para la obtención de licencias de vacunas. El virus de la enfermedad de Marek (MDV) es un patógeno importante en la avicultura que se controla mediante la vacunación generalizada con cepas avirulentas y atenuadas. Sin embargo, la evolución continua de los virus de campo hacia una mayor virulencia ha requerido una mejora continua de las cepas vacunales disponibles y estas cepas vacunales ofrecen una plataforma atractiva para diseñar vacunas con vectores recombinantes que induzcan protección cruzada contra el virus de la enfermedad de Marek y patógenos adicionales. Los reportes recientes de fallas en los controles positivos para alcanzar niveles apropiadamente altos de incidencia de la enfermedad de Marek en los ensayos para obtener la licencia de vacunas llevaron a evaluar posibles combinaciones de líneas de postura híbridas libres de patógenos específicos y cepas de desafío virulentas alternativas que podrían proporcionar modelos más consistentes para el desarrollo de vacunas con vectores de serotipo 3. Tanto la elección de la línea de postura como de la cepa de desafío virulenta de Marek contribuyeron a obtener un modelo de desafío con capacidad para alcanzar el 80% de virulencia en grupos controles positivo no vacunados en la mayoría de los ensayos, sin una protección abrumadora de la vacuna con vector de serotipo 3 en los grupos vacunados. Por el contrario, la reducción de la dosis del virus de desafío en un factor de cuatro, o la dosis de vacuna a la mitad, no tuvieron un efecto constante en estos modelos. Aunque la cepa 617A de Marek mostró el mayor potencial como alternativa a las cepas que actualmente están aprobadas para ensayos de licenciar vacunas, ninguna combinación de línea de postura y virus de desafío cumplió consistentemente los objetivos de un modelo de desafío exitoso en todas las réplicas del estudio, lo que indica que la alta variabilidad es una dificultad inherente en los estudios de desafío para la enfermedad de Marek, al menos cuando se utilizan aves híbridas.

Nanoparticles as a novel and promising antiviral platform in veterinary medicine.

Traditional veterinary virus vaccines, such as inactivated and live-attenuated vaccines, have achieved tremendous success in controlling many viral diseases of livestock and chickens worldwide. However, many recent viral outbreaks caused by different emerging and re-emerging viruses continue to be reported annually worldwide. It is therefore necessary to develop new control regimens. Nanoparticle research has received considerable attention in the last two decades as a promising platform with significant success in veterinary medicine, replacing traditional viral vector vaccines. However, the field of nanoparticle applications is still in its initial phase of growth. Here, we discuss various preparation methods, characteristics, physical properties, antiviral effects, and pharmacokinetics of well-developed nanoparticles and the potential of nanoparticles or nano-vaccines as a promising antiviral platform for veterinary medicine.

Glycoconjugate vaccines: classic and novel approaches.

Glycoconjugate vaccines, obtained by carbohydrates covalently bound to protein carriers, have contributed to fight diseases such as meningitidis, pneumonia and typhoid fever. Despite new technologies such as RNA and adenovirus based vaccine have now reached the market, these approaches are unable to target carbohydrates which are key virulence factors.This issue intends to provide an overview on relevant directions where the field is evolving and serve as starting point to increase interest in this exciting and fundamental part of vaccinology.

Thoughts on African Swine Fever Vaccines.

African swine fever (ASF) is an acute viral hemorrhagic disease of domestic swine with mortality rates approaching 100%. Devastating ASF outbreaks and continuing epidemics starting in the Caucasus region and now in the Russian Federation, Europe, China, and other parts of Southeast Asia (2007 to date) highlight its significance. ASF strain Georgia-07 and its derivatives are now endemic in extensive regions of Europe and Asia and are "out of Africa" forever, a situation that poses a grave if not an existential threat to the swine industry worldwide. While our current concern is Georgia-07, other emerging ASFV strains will threaten for the indefinite future. Economic analysis indicates that an ASF outbreak in the U.S. would result in approximately $15 billion USD in losses, assuming the disease is rapidly controlled and the U.S. is able to reenter export markets within two years. ASF's potential to spread and become endemic in new regions, its rapid and efficient transmission among pigs, and the relative stability of the causative agent ASF virus (ASFV) in the environment all provide significant challenges for disease control. Effective and robust methods, including vaccines for ASF response and recovery, are needed immediately.

Characterisation of an Australian fowlpox virus carrying a near-full-length provirus of reticuloendotheliosis virus.

Fowlpox virus (FWPV), which is the type member of the genus Avipoxvirus, subfamily Chordopoxvirinae, family Poxviridae, can lead to significant losses to the poultry industry. Although a large number of fowlpox virus genomes have been sequenced and characterised globally, there are no sequences available at the genomic level from Australian isolates. Here, we present the first complete genome sequence of a fowlpox virus vaccine strain (FWPV-S) containing an integrated near-full-length reticuloendotheliosis virus (REV) provirus. The genome of FWPV-S showed the highest sequence similarity to a fowlpox virus from the USA (97.74% identity). The FWPV-S genome contained 16 predicted unique genes, while a further two genes were fragmented compared to previously reported FWPV genome sequences. Subsequent phylogenetic analysis showed that FWPV-S was most closely related to other fowlpox viruses. This is the first reported genome sequence of FWPV from Australia.

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Intranasal inoculations of naked or PLGA-PEI nanovectored DNA vaccine induce systemic and mucosal antibodies in pigs: A feasibility study.

Mucosa are the routes of entry of most pathogens into animals' organisms. Reducing the important global burden of mucosal infectious diseases in livestock animals is required in the field of veterinary public health. For veterinary respiratory pathogens, one possible strategy is the development of intranasal (IN) DNA vaccination. The aim of this study was to assess the feasibility of IN DNA vaccination in pigs, an important species in livestock production industry, and a source of zoonotic diseases. To achieve this goal, we used a DNA vaccine against pseudorabies virus (PrV) encoding the immunogenic glycoprotein B (pcDNA3-gB plasmid). When pigs were inoculated with the naked DNA vaccine through the IN route, PrV-specific IgG and IgA type antibodies were detected in porcine sera. Interestingly, mucosal salivary IgA antibodies against PrV were also detected, at similar levels to those measured following intramuscular injection (positive controls). Furthermore, the IN delivery of pcDNA3-gB combined with PLGA-PEI nanoparticles resulted in similar levels of antibodies but was associated with an increase in the duration of detection of mucosal IgA for 2 out of 3 pigs. Our results suggest that there is room to improve the efficacy of IN DNA vaccination in pigs through optimization of IN inoculations, for example by using nanoparticles such as PLGA-PEI. Further studies will be dedicated to optimizing and testing the protective potential of IN DNA vaccination procedures against PrV.

Experimental evaluation of the cross-protection between Sheeppox and bovine Lumpy skin vaccines.

The Capripoxvirus genus includes three agents: Sheeppox virus, Goatpox virus and Lumpy skin disease virus. Related diseases are of economic importance and present a major constraint to animals and animal products trade in addition to mortality and morbidity. Attenuated vaccines against these diseases are available, but afforded cross-protection is controversial in each specie. In this study, groups of sheep, goats and cattle were vaccinated with Romania SPPV vaccine and challenged with corresponding virulent strains. Sheep and cattle were also vaccinated with Neethling LSDV vaccine and challenged with both virulent SPPV and LSDV strains. Animals were monitored by clinical observation, rectal temperature as well as serological response. The study showed that sheep and goats vaccinated with Romania SPPV vaccine were fully protected against challenge with virulent SPPV and GTPV strains, respectively. However, small ruminants vaccinated with LSDV Neethling vaccine showed only partial protection against challenge with virulent SPPV strain. Cattle showed also only partial protection when vaccinated with Romania SPPV and were fully protected with Neethling LSDV vaccine. This study showed that SPPV and GTPV vaccines are closely related with cross-protection, while LSDV protects only cattle against the corresponding disease, which suggests that vaccination against LSDV should be carried out with homologous strain.

Effect of essential oils on the immune response to some viral vaccines in broiler chickens, with special reference to Newcastle disease virus.

This trial assessed the efficacy of a commercial essential oil (EO) product on the immune response to vaccination against Newcastle disease (ND) and subsequent challenge with virulent ND virus genotype VII (vNDv genotype VII) by using the following experimental groups of broiler chickens (Each group had 21 birds with 3 replicates in each, n = 7): NC (negative control), PC (positive control), VC (vaccinated), and VTC (vaccinated and treated with EOs). Moreover, in a trial to study the effect of EOs on vNDv genotype VII in vivo as a preventive or therapeutic measure, 2 additional ND-vaccinated groups were used (PRV: medicated 1 D before vNDv challenge for 5 D; and TTT: medicated 2 D after vNDv challenge for 5 D). In addition, the immune-modulatory effect of EOs on the avian influenza (AI), infectious bronchitis (IB), and infectious bursal disease (IBD) vaccines was assessed through the serological response. The use of EOs along with administration of ND vaccines (VTC) revealed a lower mortality rate (42.86%), clinical signs, and postmortem lesion score (11) than ND vaccines alone (VC) (52.28% mortality and score 15), in addition to lower hemagglutination inhibition (P < 0.05) (6.5 ± 0.46) and viral shedding (10 log 2.28 ± 0.24) titres 1 wk after challenge in comparison with VC (8.63 ± 0.65 and 10 log 3.29 ± 0.72, respectively). Nevertheless, the EOs mixture (VTC) (1952 ± 28.82) did not significantly (P > 0.05) improve growth performance compared with the nontreated birds (NC and VC) (1970 ± 19.56 and 1904 ± 38.66). EOs showed an antiviral effect on vNDv in vivo (in chickens) as a preventive measure (PRV) as well as some therapeutic effect (TTT) through decreasing the viral shedding titres (loNC0), mortality rate, and severity of clinical signs and postmortem lesions, in addition to serum malondialdhyde level. Regarding the other viruses, the EOs mixture did not improve the immune response to the AI and IB vaccines but significantly (P < 0.05) increased the ELISA antibody titre for IBD virus at the 28th D of age (2,108 ± 341.05). The studied EOs mixture showed an immune-stimulating response to ND and IBD vaccines, antiviral effect against ND virus, especially if administered before the challenge; however, it did not have a growth-promoting effect.

Towards effective COVID­19 vaccines: Updates, perspectives and challenges (Review).

In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS­COV­2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID­19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.

From SARS-CoV to SARS-CoV-2: safety and broad-spectrum are important for coronavirus vaccine development.

The global pandemic of COVID-19 caused by SARS-CoV-2 (also known as 2019-nCoV and HCoV-19) has posed serious threats to public health and economic stability worldwide, thus calling for development of vaccines against SARS-CoV-2 and other emerging and reemerging coronaviruses. Since SARS-CoV-2 and SARS-CoV have high similarity of their genomic sequences and share the same cellular receptor (ACE2), it is essential to learn the lessons and experiences from the development of SARS-CoV vaccines for the development of SARS-CoV-2 vaccines. In this review, we summarized the current knowledge on the advantages and disadvantages of the SARS-CoV vaccine candidates and prospected the strategies for the development of safe, effective and broad-spectrum coronavirus vaccines for prevention of infection by currently circulating SARS-CoV-2 and other emerging and reemerging coronaviruses that may cause future epidemics or pandemics.

Toward peste des petits virus (PPRV) eradication: Diagnostic approaches, novel vaccines, and control strategies.

Peste des petits ruminants (PPR) is an acute transboundary infectious viral disease affecting domestic and wild small ruminants' species besides camels reared in Africa, Asia and the Middle East. The virus is a serious paramount challenge to the sustainable agriculture advancement in the developing world. The disease outbreak was also detected for the first time in the European Union namely in Bulgaria at 2018. Therefore, the disease has lately been aimed for eradication with the purpose of worldwide clearance by 2030. Radically, the vaccines needed for effectively accomplishing this aim are presently convenient; however, the availableness of innovative modern vaccines to fulfill the desideratum for Differentiating between Infected and Vaccinated Animals (DIVA) may mitigate time spent and financial disbursement of serological monitoring and surveillance in the advanced levels for any disease obliteration campaign. We here highlight what is at the present time well-known about the virus and the different available diagnostic tools. Further, we interject on current updates and insights on several novel vaccines and on the possible current and prospective strategies to be applied for disease control.

Experimental lumpy skin disease virus infection of cattle: comparison of a field strain and a vaccine strain.

Lumpy skin disease virus (LSDV) infections can cause massive clinical signs in cattle and have great economic impact due to severe trade restrictions. For LSDV control, only live attenuated vaccines are commercially available, but they currently are not authorized in the European Union. Moreover, these vaccine virus strains can induce substantial side effects with clinical signs similar to infections with virulent LSDV. In our study, we compared clinical symptoms, viremia, and seroconversion of cattle inoculated either with a virulent field strain from North Macedonia isolated from diseased cattle in 2016 or with the attenuated LSDV vaccine strain "Neethling". Using specimens from the field and from experimental inoculation, different diagnostic tools, including a pan-capripox real-time qPCR, newly developed duplex real-time qPCR assays for differentiation between virulent and attenuated LSDV strains, and several serological methods (ELISA, indirect immunofluorescence test and serum neutralization test [SNT]) were evaluated. Our data show a high analytical sensitivity of both tested duplex real-time qPCR systems for the reliable distinction of LSDV field and vaccine strains. Moreover, the commercially available capripox double-antigen ELISA seems to be as specific as the SNT and therefore provides an excellent tool for rapid and simple serological examination of LSDV-vaccinated or infected cattle.

A review of Lassa fever vaccine candidates.

Lassa fever is a zoonotic disease caused by the Lassa virus, a rodent-borne arenavirus endemic to West Africa. Recent steady increase in reported cases of the disease in Nigeria, where 123 deaths occurred in 546 confirmed cases in 2019 has further underlined the need to accelerate the development of vaccines for preventing the disease. Intensified research and development of Lassa fever medical countermeasures have yielded some vaccine candidates with preclinical scientific plausibility using predominantly novel technology. The more advanced candidates are based on recombinant measles, Vesicular Stomatitis Virus or Mopiea and Lassa virus reassortants expressing Lassa virus antigens, and the deoxyribonucleic acid platform. However, the Lassa fever portfolio still lags behind other neglected tropical diseases', and further investments are needed for continued development and additional research, such as the safety and efficacy of these vaccine candidates in special populations.

Chicken Embryonic-Stem Cells Are Permissive to Poxvirus Recombinant Vaccine Vectors.

The discovery of mammalian pluripotent embryonic stem cells (ESC) has revolutionised cell research and regenerative medicine. More recently discovered chicken ESC (cESC), though less intensively studied, are increasingly popular as vaccine substrates due to a dearth of avian cell lines. Information on the comparative performance of cESC with common vaccine viruses is limited. Using RNA-sequencing, we compared cESC transcriptional programmes elicited by stimulation with chicken type I interferon or infection with vaccine viruses routinely propagated in primary chicken embryo fibroblasts (CEF). We used poxviruses (fowlpox virus (FWPV) FP9, canarypox virus (CNPV), and modified vaccinia virus Ankara (MVA)) and a birnavirus (infectious bursal disease virus (IBDV) PBG98). Interferon-stimulated genes (ISGs) were induced in cESC to levels comparable to those in CEF and immortalised chicken fibroblast DF-1 cells. cESC are permissive (with distinct host transcriptional responses) to MVA, FP9, and CNPV but, surprisingly, not to PBG98. MVA, CNPV, and FP9 suppressed innate immune responses, while PBG98 induced a subset of ISGs. Dysregulation of signalling pathways (i.e., NFκB, TRAF) was observed, which might affect immune responses and viral replication. In conclusion, we show that cESC are an attractive alternative substrate to study and propagate poxvirus recombinant vaccine vectors.

Usefulness of a systematic approach at listing for vaccine prevention in solid organ transplant candidates.

Solid organ transplant (SOT) candidates may not be immune against potentially vaccine-preventable diseases because of insufficient immunizations and/or limited vaccine responses. We evaluated the impact on vaccine immunity at transplant of a systematic vaccinology workup at listing that included (1) pneumococcal with and without influenza immunization, (2) serology-based vaccine recommendations against measles, varicella, hepatitis B virus, hepatitis A virus, and tetanus, and (3) the documentation of vaccines and serology tests in a national electronic immunization registry (www.myvaccines.ch). Among 219 SOT candidates assessed between January 2014 and November 2015, 54 patients were transplanted during the study. Between listing and transplant, catch-up immunizations increased the patients' immunity from 70% to 87% (hepatitis A virus, P = .008), from 22% to 41% (hepatitis B virus, P = .008), from 77% to 91% (tetanus, P = .03), and from 78% to 98% (Streptococcus pneumoniae, P = .002). Their immunity at transplant was significantly higher against S. pneumoniae (P = .006) and slightly higher against hepatitis A virus (P = .07), but not against hepatitis B virus, than that of 65 SOT recipients transplanted in 2013. This demonstrates the value of a systematic multimodal serology-based approach of immunizations of SOT candidates at listing and the need for optimized strategies to increase their hepatitis B virus vaccine responses.

Vaccination of carp against SVCV with an oral DNA vaccine or an insect cells-based subunit vaccine.

We recently reported on a successful vaccine for carp against SVCV based on the intramuscular injection of a DNA plasmid encoding the SVCV glycoprotein (SVCV-G). This shows that the intramuscular (i.m.) route of vaccination is suitable to trigger protective responses against SVCV, and that the SVCV G-protein is a suitable vaccine antigen. Yet, despite the general success of DNA vaccines, especially against fish rhabdoviruses, their practical implementation still faces legislative as well as consumer's acceptance concerns. Furthermore, the i.m. route of plasmid administration is not easily combined with most of the current vaccination regimes largely based on intraperitoneal or immersion vaccination. For this reason, in the current study we evaluated possible alternatives to a DNA-based i.m. injectable vaccine using the SVCV-G protein as the vaccine antigen. To this end, we tested two parallel approaches: the first based on the optimization of an alginate encapsulation method for oral delivery of DNA and protein antigens; the second based on the baculovirus recombinant expression of transmembrane SVCV-G protein in insect cells, administered as whole-cell subunit vaccine through the oral and injection route. In addition, in the case of the oral DNA vaccine, we also investigated the potential benefits of the mucosal adjuvants Escherichia coli lymphotoxin subunit B (LTB). Despite the use of various vaccine types, doses, regimes, and administration routes, no protection was observed, contrary to the full protection obtained with our reference i.m. DNA vaccine. The limited protection observed under the various conditions used in this study, the nature of the host, of the pathogen, the type of vaccine and encapsulation method, will therefore be discussed in details to provide an outlook for future vaccination strategies against SVCV.

DNA vaccination for finfish aquaculture.

In fish, DNA vaccines have been shown to give very high protection in experimental facilities against a number of viral diseases, particularly diseases caused by rhabdoviruses. However, their efficacy in generating protection against other families of fish viral pathogens is less clear. One DNA vaccine is currently in use commercially in fish farms in Canada and the commercialisation of another was authorised in Europe in 2017. The mechanism of action of DNA vaccines, including the role of the innate immune responses induced shortly after DNA vaccination in the activation of the adaptive immunity providing longer term specific protection, is still not fully understood. In Europe the procedure for the commercialisation of a veterinary DNA vaccine requires the resolution of certain concerns particularly about safety for the host vaccinated fish, the consumer and the environment. Relating to consumer acceptance and particularly environmental safety, a key question is whether a DNA vaccinated fish is considered a Genetically Modified Organism (GMO). In the present opinion paper these key aspects relating to the mechanisms of action, and to the development and the use of DNA vaccines in farmed fish are reviewed and discussed.