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The Journal of Infectious Diseases Jun 2014Chikungunya virus (CHIKV) causes outbreaks of chikungunya fever worldwide and represents an emerging pandemic threat. Vaccine development against CHIKV has proved...
BACKGROUND
Chikungunya virus (CHIKV) causes outbreaks of chikungunya fever worldwide and represents an emerging pandemic threat. Vaccine development against CHIKV has proved challenging. Currently there is no approved vaccine or specific therapy for the disease.
METHODS
To develop novel experimental CHIKV vaccine, we used novel immunization DNA (iDNA) infectious clone technology, which combines the advantages of DNA and live attenuated vaccines. Here we describe an iDNA vaccine composed of plasmid DNA that encode the full-length infectious genome of live attenuated CHIKV clone 181/25 downstream from a eukaryotic promoter. The iDNA approach was designed to initiate replication of live vaccine virus from the plasmid in vitro and in vivo.
RESULTS
Experimental CHIKV iDNA vaccines were prepared and evaluated in cultured cells and in mice. Transfection with 10 ng of iDNA was sufficient to initiate replication of vaccine virus in vitro. Vaccination of BALB/c mice with a single 10 μg of CHIKV iDNA plasmid resulted in seroconversion, elicitation of neutralizing antibodies, and protection from experimental challenge with a neurovirulent CHIKV.
CONCLUSIONS
Live attenuated CHIKV 181/25 vaccine can be delivered in vitro and in vivo by using DNA vaccination. The iDNA approach appears to represent a promising vaccination strategy for CHIK and other alphaviral diseases.
Topics: Alphavirus Infections; Animals; Antibodies, Neutralizing; Antibodies, Viral; Chikungunya Fever; Chikungunya virus; Cloning, Molecular; DNA, Viral; Female; Mice; Mice, Inbred BALB C; Vaccines, Attenuated; Vaccines, DNA; Viral Vaccines; Virus Replication
PubMed: 24585894
DOI: 10.1093/infdis/jiu114 -
Frontiers in Cellular and Infection... 2013Burkholderia mallei and Burkholderia pseudomallei are Gram-negative bacteria that cause glanders and melioidosis, respectively. Inhalational infection with either... (Review)
Review
Burkholderia mallei and Burkholderia pseudomallei are Gram-negative bacteria that cause glanders and melioidosis, respectively. Inhalational infection with either organism can result in severe and rapidly fatal pneumonia. Inoculation by the oral and cutaneous routes can also produce infection. Chronic infection may develop after recovery from acute infection with both agents, and control of infection with antibiotics requires prolonged treatment. Symptoms for both meliodosis and glanders are non-specific, making diagnosis difficult. B. pseudomallei can be located in the environment, but in the host, B. mallei and B. psedomallei are intracellular organisms, and infection results in similar immune responses to both agents. Effective early innate immune responses are critical to controlling the early phase of the infection. Innate immune signaling molecules such as TLR, NOD, MyD88, and pro-inflammatory cytokines such as IFN-γ and TNF-α play key roles in regulating control of infection. Neutrophils and monocytes are critical cells in the early infection for both microorganisms. Both monocytes and macrophages are necessary for limiting dissemination of B. pseudomallei. In contrast, the role of adaptive immune responses in controlling Burkholderia infection is less well understood. However, T cell responses are critical for vaccine protection from Burkholderia infection. At present, effective vaccines for prevention of glanders or meliodosis have not been developed, although recently development of Burkholderia vaccines has received renewed attention. This review will summarize current and past approaches to develop B. mallei and B. pseudomalllei vaccines, with emphasis on immune mechanisms of protection and the challenges facing the field. At present, immunization with live attenuated bacteria provides the most effective and durable immunity, and it is important therefore to understand the immune correlates of protection induced by live attenuated vaccines. Subunit vaccines have typically provided less robust immunity, but are safer to administer to a wider variety of people, including immune compromised individuals because they do not reactivate or cause disease. The challenges facing B. mallei and B. pseudomalllei vaccine development include identification of broadly protective antigens, design of efficient vaccine delivery and adjuvant systems, and a better understanding of the correlates of protection from both acute and chronic infection.
Topics: Animals; Antigens, Bacterial; Bacterial Vaccines; Burkholderia mallei; Burkholderia pseudomallei; Drug Discovery; Glanders; Humans; Melioidosis; Vaccines, Attenuated; Vaccines, Subunit
PubMed: 23508691
DOI: 10.3389/fcimb.2013.00010 -
Viruses May 2020Live-attenuated vaccines (LAVs) have achieved remarkable successes in controlling virus spread, as well as for other applications such as cancer immunotherapy. However,... (Review)
Review
Live-attenuated vaccines (LAVs) have achieved remarkable successes in controlling virus spread, as well as for other applications such as cancer immunotherapy. However, with rapid increases in international travel, globalization, geographic spread of viral vectors, and widespread use of vaccines, there is an increasing need to consider how pre-exposure to viruses which share similar antigenic regions can impact vaccine efficacy. Pre-existing antibodies, derived from either from maternal-fetal transmission, or by previous infection or vaccination, have been demonstrated to interfere with vaccine immunogenicity of measles, adenovirus, and influenza LAVs. Immune interference of LAVs can be caused by the formation of virus-antibody complexes that neutralize virus infection in antigen-presenting cells, or by the cross-linking of the B-cell receptor with the inhibitory receptor, FcgRIIB. On the other hand, pre-existing antibodies can augment flaviviral LAV efficacy such as that of dengue and yellow fever virus, especially when pre-existing antibodies are present at sub-neutralizing levels. The increased vaccine immunogenicity can be facilitated by antibody-dependent enhancement of virus infection, enhancing virus uptake in antigen-presenting cells, and robust induction of innate immune responses that promote vaccine immunogenicity. This review examines the literature on this topic and examines the circumstances where pre-existing antibodies can inhibit or enhance LAV efficacy. A better knowledge of the underlying mechanisms involved could allow us to better manage immunization in seropositive individuals and even identify possibilities that could allow us to exploit pre-existing antibodies to boost vaccine-induced responses for improved vaccine efficacy.
Topics: Animals; Antibodies, Viral; Humans; Immunogenicity, Vaccine; Vaccines, Attenuated; Viral Vaccines; Virus Diseases; Viruses
PubMed: 32397218
DOI: 10.3390/v12050520 -
MBio Apr 2019Tick-borne encephalitis virus (TBEV), a member of the genus , is one of the most medically important tick-borne pathogens of the Old World. Despite decades of active...
Stable and Highly Immunogenic MicroRNA-Targeted Single-Dose Live Attenuated Vaccine Candidate against Tick-Borne Encephalitis Constructed Using Genetic Backbone of Langat Virus.
Tick-borne encephalitis virus (TBEV), a member of the genus , is one of the most medically important tick-borne pathogens of the Old World. Despite decades of active research, attempts to develop of a live attenuated virus (LAV) vaccine against TBEV with acceptable safety and immunogenicity characteristics have not been successful. To overcome this impasse, we generated a chimeric TBEV that was highly immunogenic in nonhuman primates (NHPs). The chimeric virus contains the prM/E genes of TBEV, which are expressed in the genetic background of an antigenically closely related, but less pathogenic member of the TBEV complex-Langat virus (LGTV), strain T-1674. The neurovirulence of this chimeric virus was subsequently controlled by robust targeting of the viral genome with multiple copies of central nervous system-enriched microRNAs (miRNAs). This miRNA-targeted T/1674-mirV2 virus was highly stable in Vero cells and was not pathogenic in various mouse models of infection or in NHPs. Importantly, in NHPs, a single dose of the T/1674-mirV2 virus induced TBEV-specific neutralizing antibody (NA) levels comparable to those seen with a three-dose regimen of an inactivated TBEV vaccine, currently available in Europe. Moreover, our vaccine candidate provided complete protection against a stringent wild-type TBEV challenge in mice and against challenge with a parental (not miRNA-targeted) chimeric TBEV/LGTV in NHPs. Thus, this highly attenuated and immunogenic T/1674-mirV2 virus is a promising LAV vaccine candidate against TBEV and warrants further preclinical evaluation of its neurovirulence in NHPs prior to entering clinical trials in humans. Tick-borne encephalitis virus (TBEV) is one of the most medically important tick-borne pathogens of the Old World. Despite decades of active research, efforts to develop of TBEV live attenuated virus (LAV) vaccines with acceptable safety and immunogenicity characteristics have not been successful. Here we report the development and evaluation of a highly attenuated and immunogenic microRNA-targeted TBEV LAV.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Chlorocebus aethiops; Drug Carriers; Encephalitis Viruses, Tick-Borne; Encephalitis, Tick-Borne; Genetic Vectors; Mice; MicroRNAs; Vaccines, Attenuated; Vaccines, Synthetic; Vero Cells; Viral Vaccines; Virus Replication
PubMed: 31015334
DOI: 10.1128/mBio.02904-18 -
Emerging Microbes & Infections Dec 2024Genetic changes have occurred in the genomes of prevalent African swine fever viruses (ASFVs) in the field in China, which may change their antigenic properties and...
Genetic changes have occurred in the genomes of prevalent African swine fever viruses (ASFVs) in the field in China, which may change their antigenic properties and result in immune escape. There is usually poor cross-protection between heterogonous isolates, and, therefore, it is important to test the cross-protection of the live attenuated ASFV vaccines against current prevalent heterogonous isolates. In this study, we evaluated the protective efficacy of the ASFV vaccine candidate HLJ/18-7GD against emerging isolates. HLJ/18-7GD provided protection against a highly virulent variant and a lower lethal isolate, both derived from genotype II Georgia07-like ASFV and isolated in 2020. HLJ/18-7GD vaccination prevented pigs from developing ASF-specific clinical signs and death, decreased viral shedding via the oral and rectal routes, and suppressed viral replication after challenges. However, HLJ/18-7GD vaccination did not provide solid cross-protection against genotype I NH/P68-like ASFV challenge in pigs. HLJ/18-7GD vaccination thus shows great promise as an alternative strategy for preventing and controlling genotype II ASFVs, but vaccines providing cross-protection against different ASFV genotypes may be needed in China.
Topics: Swine; Animals; African Swine Fever; Vaccines, Attenuated; Viral Proteins; African Swine Fever Virus; Genotype; Viral Vaccines
PubMed: 38164797
DOI: 10.1080/22221751.2023.2300464 -
Acta Veterinaria Scandinavica Mar 2018The intracellular bacterium Lawsonia intracellularis is an important pathogen in modern swine production. The aim of this study was to investigate the effect of a live...
BACKGROUND
The intracellular bacterium Lawsonia intracellularis is an important pathogen in modern swine production. The aim of this study was to investigate the effect of a live attenuated L. intracellularis vaccine (Enterisol Ileitis) on the health and production parameters of weaned and finishing pigs in a commercial Finnish 850-sow farm with diagnosed L. intracellularis infection. The herd was free from enzootic pneumonia, swine dysentery, progressive atrophic rhinitis, sarcoptic mange and salmonellosis. Four weekly groups of approximately 500 piglets were included in the study for a total of approximately 2000 piglets. Half of these piglets were vaccinated at 3 weeks of age and the other half served as controls. The study piglets were ear-tagged with individual numbers and colour-coded and were individually weighed at weaning (4 weeks), delivery to the finishing farm (12-14 weeks) and at slaughter. Mortality, symptoms of diseases and medications of the study piglets were registered in the nursery and finishing unit. Feed conversion rate was calculated for the finishing period and lean meat percentage was measured at slaughter.
RESULTS
Vaccinated piglets had a higher live weight than unvaccinated piglets at delivery to the finishing unit (+ 1.18 kg, P = 0.002) and at slaughter (+ 3.57 kg, P < 0.001). The daily weight gain of vaccinated piglets was better than unvaccinated piglets in the nursery (+ 14.8 g/d, P = 0.013) and in the finishing unit (+ 30.9 g/d, P < 0.001). Vaccination had no effect on feed conversion rate or lean meat percentage (P = 0.102). Altogether, 3.9 and 4.6% of the pigs were medicated for different reasons in the vaccinated and control groups, respectively. The return on investment for the vaccination was calculated to be 0.41.
CONCLUSIONS
Immunisation of piglets with a live attenuated L. intracellularis vaccine resulted in higher meat yield in pig production via significantly higher live weight and average daily weight gain in a Finnish specific pathogen-free setting.
Topics: Animals; Anti-Infective Agents; Bacterial Vaccines; Desulfovibrionaceae Infections; Energy Metabolism; Female; Finland; Lawsonia Bacteria; Sus scrofa; Swine; Swine Diseases; Vaccines, Attenuated; Weight Gain
PubMed: 29566718
DOI: 10.1186/s13028-018-0374-8 -
Vaccine Dec 2017Zoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from... (Review)
Review
BACKGROUND
Zoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from clinical trials and post-licensure studies provided reassurance that ZVL is generally safe and well tolerated. The objective of this review was to provide worldwide post-marketing safety information following 10 years of use and >34 million doses distributed.
METHODS
All post-marketing adverse experience (AE) reports received worldwide between 02-May-2006 and 01-May-2016 from healthcare professionals following vaccination with ZVL and submitted to the MSD AE global safety database, were analyzed.
RESULTS
A total of 23,556 AE reports, 93% non-serious, were reported. Local injection site reactions (ISRs), with a median time-to-onset of 2 days, were the most frequently reported AEs followed by HZ. The majority of HZ reports were reported within 2 weeks of vaccination and considered, based on time-to-onset, pathogenesis of HZ, and data from clinical trials, to be caused by wild-type varicella-zoster virus (VZV). HZ confirmed by PCR analysis to be VZV Oka/Merck vaccine-strain was identified in an immunocompetent individual 8 months postvaccination and in 4 immunocompromised individuals. Disseminated HZ was reported very rarely (<1%) with 38% occurring in immunocompromised individuals. All reports of disseminated HZ confirmed by PCR as VZV Oka/Merck vaccine-strain were in individuals with immunosuppressive conditions and/or therapy at the time of vaccination.
CONCLUSIONS
The safety profile of ZVL, following 10 years of post-marketing use, was favorable and consistent with that observed in clinical trials and post-licensure studies.
Topics: Aged; Antibodies, Viral; Clinical Trials as Topic; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Eye; Female; Herpes Zoster; Herpes Zoster Vaccine; Herpesvirus 3, Human; Humans; Immunocompromised Host; Male; Middle Aged; Polymerase Chain Reaction; Product Surveillance, Postmarketing; Vaccination; Vaccines, Attenuated
PubMed: 29174682
DOI: 10.1016/j.vaccine.2017.11.013 -
Vector Borne and Zoonotic Diseases... Nov 2022The emergence or re-emergence of several orthobunyaviruses (order: ; family: ), including Cache Valley virus (CVV) and Oropouche virus, warrants the development and...
The emergence or re-emergence of several orthobunyaviruses (order: ; family: ), including Cache Valley virus (CVV) and Oropouche virus, warrants the development and evaluation of candidate live-attenuated vaccines (LAVs). Ideally, these vaccines would elicit long-lasting immunity with one single immunization. Since the deletion of two virulence factors, NSs and NSm, has been shown to attenuate the virulence phenotype of orthobunyaviruses, phleboviruses, and nairoviruses, genetic manipulation of the viral genome is considered an effective strategy for the rational design of candidate LAVs for bunyaviruses across multiple families. In addition, the deletion of Rift Valley fever virus NSs and NSm genes has been shown to reduce transmission by mosquitoes. In this study, the ability of a CVV mutant lacking the NSs and NSm genes (2delCVV) to replicate in intrathoracically injected was compared with the parental wild-type CVV (wtCVV) 6V633 strain. In contrast to the robust replication of wtCVV in injected mosquitoes, the multiplication kinetics of the 2delCVV mutant was reduced by more than a 100-fold. These results suggest that the deletion of NSm and NSs genes is a feasible approach to rationally design candidate orthobunyavirus LAVs that are highly attenuated in mosquitoes and, therefore, pose little risk of reversion to virulence and transmission.
Topics: Animals; Bunyamwera virus; Aedes; Vaccines, Attenuated; Kinetics; Rift Valley fever virus; Viral Vaccines; Virus Replication; Rift Valley Fever
PubMed: 36354965
DOI: 10.1089/vbz.2022.0053 -
The Lancet. Infectious Diseases Jan 2023Live attenuated vaccines could have beneficial, non-specific effects of protecting against vaccine-unrelated infections, such as BCG protecting against respiratory... (Review)
Review
Live attenuated vaccines could have beneficial, non-specific effects of protecting against vaccine-unrelated infections, such as BCG protecting against respiratory infection. During the COVID-19 pandemic, testing of these effects against COVID-19 was of interest to the pandemic control programme. Non-specific effects occur due to the broad effects of specific live attenuated vaccines on the host immune system, relying on heterologous lymphocyte responses and induction of trained immunity. Knowledge of non-specific effects has been developed in randomised controlled trials and observational studies with children, but examining of whether the same principles apply to adults and older adults was of interest to researchers during the pandemic. In this Personal View, we aim to define a framework for the analysis of non-specific effects of live attenuated vaccines against vaccine-unrelated infections with pandemic potential using several important concepts. First, study endpoints should prioritise severity of infection and overall patient health rather than incidence of infection only (eg, although several trials found no protection of the BCG vaccine against COVID-19 infection, it is associated with lower overall mortality than placebo). Second, revaccination of an individual with the same live attenuated vaccine could be the most effective strategy against vaccine-unrelated infections. Third, coadministration of several live attenuated vaccines might enhance beneficial non-specific effects. Fourth, the sequence of vaccine administration matters; the live attenuated vaccine should be the last vaccine administered before exposure to the pandemic infection and non-live vaccines should not be administered afterwards. Fifth, live attenuated vaccines could modify the immune response to specific COVID-19 vaccines. Finally, non-specific effects of live attenuated vaccines should always be analysed with subgroup analysis by sex of individuals receiving the vaccines.
Topics: Child; Humans; Aged; COVID-19; COVID-19 Vaccines; Vaccines, Attenuated; Pandemics; Vaccination
PubMed: 36037824
DOI: 10.1016/S1473-3099(22)00498-4 -
Expert Review of Vaccines Feb 2018Traditional inactivated and protein vaccines generate strong antibodies, but struggle to generate T cell responses. Attenuated pathogen vaccines generate both, but risk... (Review)
Review
INTRODUCTION
Traditional inactivated and protein vaccines generate strong antibodies, but struggle to generate T cell responses. Attenuated pathogen vaccines generate both, but risk causing the disease they aim to prevent. Newer gene-based vaccines drive both responses and avoid the risk of infection. While these replication-defective (RD) vaccines work well in small animals, they can be weak in humans because they do not replicate antigen genes like more potent replication-competent (RC) vaccines. RC vaccines generate substantially stronger immune responses, but also risk causing their own infections. To circumvent these problems, we developed single-cycle adenovirus (SC-Ad) vectors that amplify vaccine genes, but that avoid the risk of infection. This review will discuss these vectors and their prospects for use as vaccines.
AREAS COVERED
This review provides a background of different types of vaccines. The benefits of gene-based vaccines and their ability to replicate antigen genes are described. Adenovirus vectors are discussed and compared to other vaccine types. Replication-defective, single-cycle, and replication-competent Ad vaccines are compared.
EXPERT COMMENTARY
The potential utility of these vaccines are discussed when used against infectious diseases and as cancer vaccines. We propose a move away from replication-defective vaccines towards more robust replication-competent or single-cycle vaccines.
Topics: Adenoviridae; Animals; Cancer Vaccines; Genetic Vectors; Humans; Proteins; Vaccines, Attenuated
PubMed: 29251011
DOI: 10.1080/14760584.2018.1419067