Search

A Zika self-amplifying mRNA vaccine delivered by a flexible bedside mixing formulation induces protective immunity in NHPs., Zika virus (ZIKV) is the cause of a pandemic associated with microcephaly in newborns and Guillain-Barre syndrome in adults. Currently, there are no available treatments or vaccines for ZIKV, and the development of a safe and effective vaccine is a high priority for many global health organizations. We describe the development of ZIKV vaccine candidates using the self-amplifying messenger RNA (SAM) platform technology delivered by cationic nanoemulsion (CNE) that allows bedside mixing and is particularly useful for rapid responses to pandemic outbreaks. Two immunizations of either of the two lead SAM (CNE) vaccine candidates elicited potent neutralizing antibody responses to ZIKV in mice and nonhuman primates. Both SAM (CNE) vaccines protected these animals from ZIKV challenge, with one candidate providing complete protection against ZIKV infection in nonhuman primates. The data provide a preclinical proof of concept that a SAM (CNE) vaccine candidate can rapidly elicit protective immunity against ZIKV.

Numerous candidate vaccines against cytomegalovirus (CMV) infection and disease are in development. Whereas the previous article [1] provides background and opinions about the issues relating to vaccination, this article provides specifics about the vaccines in active development, as reported at a National Institutes of Health-sponsored meeting in Bethesda on September 4–6, 2018. Here, vaccine developers provide synopses of their candidate vaccines to immunize women to protect against congenital CMV disease and to prevent the consequences of CMV disease in recipients of transplanted organs or hematopoietic stem calls. The projects are presented here roughly in the descending order of their stage of development in the opinion of the first author.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

The immunogenicity and protective efficacy of a candidate tetravalent dengue virus purified inactivated vaccine (TDENV PIV) formulated with alum or an Adjuvant System (AS01, AS03 tested at three different dose levels, or AS04) was evaluated in a 0, 1-month vaccination schedule in rhesus macaques. One month after dose 2, all adjuvanted formulations elicited robust and persisting neutralizing antibody titers against all four dengue virus serotypes. Most of the formulations tested prevented viremia after challenge, with the dengue serotype 1 and 2 virus strains administered at 40 and 32 weeks post-dose 2, respectively. This study shows that inactivated dengue vaccines, when formulated with alum or an Adjuvant System, are candidates for further development.

The transmission of cytomegalovirus (CMV) from mother to fetus can give rise to severe neurodevelopment defects in newborns. One strategy to prevent these congenital defects is prophylactic vaccination in young women. A candidate vaccine antigen is glycoprotein B (gB). This antigen is abundant on the virion surface and is a major target of neutralization responses in human infections. Here, we have evaluated in a challenge model of congenital guinea pig CMV (GPCMV) infection, GPCMV-gB vaccines formulated with the clinically relevant Adjuvant Systems AS01B and AS02V, or with Freund's adjuvant (FA). Fifty-two GPCMV-seronegative female guinea pigs were administered three vaccine doses before being mated. GPCMV-challenge was performed at Day 45 of pregnancy (of an estimated 65 day gestation). Pup mortality rates in the gB/AS01B, gB/AS02V, and gB/FA groups were 24% (8/34), 10% (4/39) and 36% (12/33), respectively, and in the unvaccinated control group was 65% (37/57). Hence, efficacies against pup mortality were estimated at 64%, 84% and 44% for gB/AS01B (p

In the context of an A/H1N1 influenza pandemic situation, this study demonstrates that heterologous vaccination with an AS03-adjuvanted 2008/2009 seasonal trivalent and pandemic H5N1 monovalent split vaccine conferred partial protection in influenza-naive ferrets after challenge with the influenza pandemic H1N1 A/The Netherlands/602/09 virus. Further, unlike saline control and non-adjuvanted vaccine, it was shown that immunization of naive ferrets with an AS03-adjuvanted pandemic H1N1 A/California/7/09 influenza split vaccine induced increased antibody response and enhanced protection against the challenge strain, including significant reduction in viral shedding in the upper respiratory tract and reduced lung pathology post-challenge. These results show the need for vaccination with the adjuvanted vaccine to fully protect against viral replication and influenza disease in unprimed ferrets. (C) 2011 Elsevier Ltd. All rights reserved.

GlaxoSmithKline Biologicals S.A. (Rixensart, Belgium) under a Cooperative Research and Development Agreement with Fiocruz(Rio de Janeiro, Brazil). GlaxoSmithKline Biologicals S.A. was involved in the study design, data collection and analysis, decision to publish and preparation of the manuscript. PFCV was partially supported by MoH and CNPq (457664/2013-4 and 303999/ 2016-0) Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rockville, Maryland, United States of America. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rockville, Maryland, United States of America. GSK. Rockville, Maryland, United States of America. GSK. Rixensart, Belgium. GSK. Rixensart, Belgium. GSK. Rixensart, Belgium. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rixensart, Belgium. The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model?s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-? and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

With the ultimate goal of developing a therapeutic cancer vaccine, we encapsulated the Her-2/neu peptide p369-377 in poly(lactide-co-glycolide) microspheres. This formulation was found to effectively elicit CD8+ cytotoxic T cell (CTL) responses in an HLA-A*0201 transgenic mouse model. In contrast, immunization with either peptide alone or peptide formulated in incomplete Freund's adjuvant (IFA) failed to elicit such CTL responses. Responses induced by the peptide-microsphere formulation were found to peak at approximately 6 weeks post-immunization, and were enhanced by delivering increased doses of peptide and with repeated administrations over time. Co-administration of the peptide-microspheres with adjuvants, including granulocyte-macrophage colony stimulating factor, MPL adjuvant and select synthetic Toll-Like Receptor 4 ligands, the aminoalkyl glucosaminide-4 phosphates, significantly augmented CTL responses. These studies provide important guidance for the design of human clinical trials of microsphere vaccines in terms of optimal peptide-microsphere formulation, vaccination regimen, vaccine dose, and adjuvant selection.

We used the pig model of influenza to examine the efficacy of an AS03(A)-adjuvanted split H5N1 (A/Indonesia/05/2005) vaccine against challenge with a low pathogenic (LP) H5N1 avian influenza (AI) virus (duck/Minnesota/1525/1981) with only 85% amino acid homology in its HA1. Influenza seronegative pigs were vaccinated twice intramuscularly with adjuvanted vaccine at 3 antigen doses, unadjuvanted vaccine or placebo. All pigs were challenged 4 weeks after the second vaccination and euthanized 2 days later. After 2 vaccinations, all pigs in the adjuvanted vaccine groups had high hemagglutination inhibiting (HI) antibody titers to the vaccine strain (160-640), and lower antibody titers to the A/Vietnam/1194/04 H5N1 strain and to 2 LP H5 viruses with 90-91% amino acid homology to the vaccine strain (20-160). Eight out of 12 pigs had HI titers (10-20) to the challenge virus immediately before challenge. Neuraminidase inhibiting antibodies to the challenge virus were detected in most pigs (7/12) and virus neutralizing antibodies in all pigs. There was no antigen-dose dependent effect on the antibody response among the pigs immunized with adjuvanted H5N1 vaccines. After challenge, these pigs showed a complete clinical protection, reduced lung lesions and a significant protection against virus replication in the respiratory tract. Though the challenge virus showed only moderate replication efficiency in pigs, our study suggests that AS03(A)-adjuvanted H5N1 vaccine may confer a broader protection than generally assumed. The pros and cons of the pig as an H5N1 challenge model are also discussed.

Lack of adequate cell-mediated immunity (CMI) to varicella-zoster virus (VZV) has been associated with higher risks of developing herpes zoster (HZ) and associated post-herpetic neuralgia (PHN), and is of particular concern for older and immunocompromised individuals. Thus, the development of an effective HZ vaccine with a clinically acceptable safety profile that is capable of addressing decreased immunity would be highly desirable. In this study we compared the immunogenicity of different vaccine formulations containing VZV glycoprotein E (gE), an important target for CMI and antibody responses, in a VZV-primed mouse model. The formulations included recombinant gE, either unadjuvanted, or combined with aluminium salt or an Adjuvant System (AS01 or AS02), and CMI was used as the primary immunological endpoint. All adjuvanted vaccines induced gE- and/or VZV-specific CD4(+) T cell and antibody responses. A formulation of gE with an Adjuvant System containing the immunostimulants QS21 and 3-O-desacyl-4'-monophosphoryl lipid A (MPL) was shown to be more immunogenic than gE with aluminium salt or unadjuvanted gE (gE/saline). Both immunostimulants were shown to act synergistically in enhancing CMI responses. Formulations with AS01 elicited high frequencies of CD4(+) T cells producing IFN-γ and IL-2. These responses were dose-dependent with respect to both antigen and adjuvant. The gE/AS01(B) candidate vaccine induced higher frequencies of CD4(+) T cells producing IL-2 and/or IFN-γ than all other gE/AS01 formulations, supporting its use for clinical evaluations.

BACKGROUND: Unprecedented spread between birds and mammals of highly pathogenic avian influenza viruses (HPAI) of the H5N1 subtype has resulted in hundreds of human infections with a high fatality rate. This has highlighted the urgent need for the development of H5N1 vaccines that can be produced rapidly and in sufficient quantities. Potential pandemic inactivated vaccines will ideally induce substantial intra-subtypic cross-protection in humans to warrant the option of use, either prior to or just after the start of a pandemic outbreak. In the present study, we evaluated a split H5N1 A/H5N1/Vietnam/1194/04, clade 1 candidate vaccine, adjuvanted with a proprietary oil-in- water emulsion based Adjuvant System proven to be well-tolerated and highly immunogenic in the human (Leroux-Roels et al. (2007) The Lancet 370:580-589), for its ability to induce intra-subtypic cross-protection against clade 2 H5N1/A/Indonesia/5/05 challenge in ferrets. METHODOLOGY AND PRINCIPAL FINDINGS: All ferrets in control groups receiving non-adjuvanted vaccine or adjuvant alone failed to develop specific or cross-reactive neutralizing antibodies and all died or had to be euthanized within four days of virus challenge. Two doses of adjuvanted split H5N1 vaccine containing >or=1.7 microg HA induced neutralizing antibodies in the majority of ferrets to both clade 1 (17/23 (74%) responders) and clade 2 viruses (14/23 (61%) responders), and 96% (22/23) of vaccinees survived the lethal challenge. Furthermore lung virus loads and viral shedding in the upper respiratory tract were reduced in vaccinated animals relative to controls suggesting that vaccination might also confer a reduced risk of viral transmission. CONCLUSION: These protection data in a stringent challenge model in association with an excellent clinical profile highlight the potential of this adjuvanted H5N1 candidate vaccine as an effective tool in pandemic preparedness.

Publisher Summary Lipopolysaccharide (LPS), the major component of the Gram-negative bacterial cell wall, has long been known as a powerful immunomodulator. Despite its well-known ability to enhance immune responses, LPS is considered too toxic by current standards to be clinically useful because of the induction of excessive amounts of inflammatory cytokines which provoke a sepsis-like syndrome. Finally, it is likely that Toll-like receptors (TLR) agonists and antagonists may enter clinical trials in the next few years as standalone immunomodulators. Intranasal administration of TLR4 agonists may protect the airways against natural infection by viruses for which there are no effective vaccines or antiviral drugs. The transient protection afforded by weekly or biweekly doses of an immunomodulatory nasal spray might prove beneficial for emerging viral infections. The broad protective ability of TLR4 agonists relative to viral and bacterial challenges make them especially well-suited for complex, multifactorial diseases in which exacerbations are most often triggered by upper respiratory viral infection. Indeed, within the immunological epiphany created by the discovery of the TLRs and their respective ligands, a new generation of designer adjuvants, therapeutic and prophylactic vaccines, and immunomodulatory therapies may be close at hand.

Research efforts over the last two decades studying immune responses to human carcinomas have demonstrated that antigens expressed by tumor cells can elicit specific cellular and humoral immune responses. Unfortunately, despite the observation that existent immune responses to these antigens are present in some patients with cancer, the tumors continue to progress. Thus, there has been considerable interest to augment these immune responses by immunization. Some of the clinical trials of the first cancer vaccines have provided evidence of clinical benefit thus encouraging the development of other vaccines. Challenges to development of such cancer vaccines include the identification and characterization of the antigen(s) to be targeted, the definition of the desired immune response to be elicited by the vaccine, and the choice of the appropriate vaccine delivery system.

Toll-like receptor (TLR) agonists are being developed for use as vaccine adjuvants and as stand-alone immunomodulators because of their ability to stimulate innate and adaptive immune responses. Among the most thoroughly studied TLR agonists are the lipid A molecules that target the TLR4 complex. One promising candidate, monophosphoryl lipid A, which is a derivative of lipid A from Salmonella minnesota, has proven to be safe and effective as a vaccine adjuvant in > 120,000 human doses. A new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs), have been engineered specifically to target human TLR4 and are showing promise as vaccine adjuvants and as monotherapeutic agents capable of eliciting nonspecific protection against a wide range of infectious pathogens. In this review, the authors provide an update of the preclinical and clinical experiences with the TLR4 agonists, MPL (Corixa Corporation) adjuvant and the AGPs.