RESUMO
Background: Programmed cell death ligand 1 (PD-L1) inhibitors have limited efficacy as monotherapy in patients with recurrent/metastatic (R/M) Human Papilloma Virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). A phase I study of the therapeutic HPV-16 DNA vaccine AMV002 in curatively treated patients with OPSCC demonstrated a measurable immune response against HPV while being associated with high safety and tolerability. This prospective phase Ib single centre pilot study aims to test the safety and tolerability of combined PD-L1 inhibitor, Durvalumab, with AMV002 in 12 patients with recurrent OPSCC. Methods: Participants had evidence of R/M HPV-associated OPSCC. They received three intradermal administrations of AMV002 with Durvalumab followed by Durvalumab maintenance. Safety and tolerability data was the primary endpoint. The study was conducted with ethical approval (HREC/2018/QMS/47293) in Brisbane, Australia. Findings: The most common adverse event (AE) related to vaccine administration was erythema at the injection site. There were no grade 3 or 4 vaccine related AEs. There was one presumed immune-related grade 3 elevation in lipase secondary to Durvalumab with no intervention required. No patient ceased study due to treatment-related AEs. At week 16, objective response rate was 8% (N=1) and disease control rate was 17% (N=2). At a median follow up of 25.6 (20.0-26.6) months there was one long term complete response while all other participants developed progressive disease. Of the 11 evaluated patients, 9, (82%) had E6 and/or E7-specific T cell responses to the vaccine. Conclusion: The combination of AMV002 therapeutic HPV-16 vaccine and Durvalumab was found to be safe and well tolerated with no increased safety signals generated. T cell responses to vaccine were observed but further work will be required to improve efficacy.
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Previous studies of CD8(+) T cell immunodominance after primary virus infection of F(1) mice compared with their inbred parents have generally concluded that no dramatic changes occur. In this study, we revisit this issue using vaccinia virus (VACV), which has a large genome, a recently defined immunodominance hierarchy in mice, and is a candidate vector for vaccines. We found that immunogenicity of VACV peptides defined using inbred mice was highly variable in F(1) progeny: some peptides were equally immunogenic in F(1) and inbred, whereas others elicited responses that were reduced by >90% in F(1) mice. Furthermore, the dominance of a peptide in the relevant inbred parent did not predict whether it would be poorly immunogenic in F(1) mice. This result held using F(1) hybrids of MHC-congenic mice, suggesting that MHC differences alone were responsible. It was also extended to foreign epitopes expressed by an rVACV vaccine. F(1) mice were less able to mount responses to the poorly immunogenic peptides when used as a sole immunogen, ruling out immunodomination. In addition, conserved TCR Vbeta usage between inbred and F(1) mice did not always correlate with strong responses in F(1) mice. However, direct estimation of naive precursor numbers showed that these were reduced in F(1) compared with inbred mice for specificities that were poorly immunogenic in the hybrids. These data have implications for our understanding of the extent to which MHC diversity alters the range of epitopes that are immunogenic in outbred populations.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos Imunodominantes/genética , Complexo Principal de Histocompatibilidade/genética , Vaccinia virus/imunologia , Vacínia/imunologia , Animais , Antígenos Virais/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Epitopos Imunodominantes/imunologia , Fenômenos Imunogenéticos , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Vacínia/genética , Vaccinia virus/genéticaRESUMO
BACKGROUND: Genital herpes simplex infection affects more than 500 million people worldwide. We have previously shown that COR-1, a therapeutic HSV-2 polynucleotide vaccine candidate, is safe and well tolerated in healthy subjects. OBJECTIVE: Here, we present a single center double-blind placebo-controlled, randomized phase I/IIa trial of COR-1 in HSV-2 positive subjects in which we assessed safety and tolerability as primary endpoints, and immunogenicity and therapeutic efficacy as exploratory endpoints. METHODS: Forty-four HSV-2+ subjects confirmed by positive serology or pathology, and positive qPCR during baseline shedding, with a recurrent genital HSV-2 history of at least 12 months including three to nine reported lesions in 12 months prior to screening, aged 18 to 50 years females and males with given written informed consent, were randomized into two groups. Three immunizations at 4-week intervals and one booster immunization at 6 months, each of 1 mg COR-1 DNA or placebo, were administered intradermally as two injections of 500 µg each to either one forearm or both forearms. RESULTS: No serious adverse events, life-threatening events or deaths occurred throughout the study. As expected, HSV-2 infected subjects displayed gD2-specific antibody titers prior to immunization. COR-1 was associated with a reduction in viral shedding after booster administration compared with baseline. CONCLUSIONS: This study confirms the previously demonstrated safety of COR-1 in humans and indicates a potential for use of COR-1 as a therapy to reduce viral shedding in HSV-2 infected subjects.
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Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/fisiologia , Imunoterapia/métodos , Polinucleotídeos/imunologia , Adolescente , Adulto , Formação de Célula em Célula , Surtos de Doenças/prevenção & controle , Método Duplo-Cego , Feminino , Herpes Genital/epidemiologia , Herpes Genital/imunologia , Humanos , Imunidade Celular/imunologia , Imunidade Humoral , Imunoterapia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Segurança , Vacinas Virais/imunologia , Eliminação de Partículas Virais , Adulto JovemRESUMO
We have previously shown that a novel DNA vaccine technology of codon optimization and the addition of ubiquitin sequences enhanced immunogenicity of a herpes simplex virus 2 polynucleotide vaccine in mice, and induced cell-mediated immunity when administered in humans at relatively low doses of naked DNA. We here show that a new polynucleotide vaccine using the same technology and encoding a fusion protein of the E6 and E7 oncogenes of high-risk human papillomavirus type 16 (HPV16) is immunogenic in mice. This vaccine induces long-lasting humoral and cell-mediated immunity and protects mice from establishment of HPV16-E7-expressing tumors. In addition, it suppresses growth of readily established tumors and shows enhanced efficacy when combined with immune checkpoint blockade targeted at PD-L1. This vaccine also facilitates rejection of HPV16-E7-expressing skin grafts that demonstrate epidermal hyperplasia with characteristics of cervical and vulvar intraepithelial neoplasia. Clinical studies evaluating the efficacy of this vaccine in patients with HPV16 premalignancies are planned.
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Rejeição de Enxerto/imunologia , Papillomavirus Humano 16/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/prevenção & controle , Animais , Anticorpos Monoclonais/administração & dosagem , Antígeno B7-H1/imunologia , Processos de Crescimento Celular , Feminino , Papillomavirus Humano 16/genética , Humanos , Imunidade Celular , Imunidade Humoral , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Proteínas Repressoras/genética , Pele/metabolismo , Transplante de Pele , Neoplasias do Colo do Útero/etiologia , Vacinação , Vacinas de DNARESUMO
This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.
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Vacinas contra o Vírus do Herpes Simples/efeitos adversos , Vacinas contra o Vírus do Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Herpesvirus Humano 2/imunologia , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia , Adulto , Anticorpos Antivirais/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Humanos , Injeções Intradérmicas , Leucócitos Mononucleares/imunologia , Masculino , Vacinas de DNA/administração & dosagem , Adulto JovemRESUMO
While there are a number of licensed veterinary DNA vaccines, to date, none have been licensed for use in humans. Here, we demonstrate that a novel technology designed to enhance the immunogenicity of DNA vaccines protects against lethal herpes simplex virus 2 (HSV-2) challenge in a murine model. Polynucleotides were modified by use of a codon optimization algorithm designed to enhance immune responses, and the addition of an ubiquitin-encoding sequence to target the antigen to the proteasome for processing and to enhance cytotoxic T cell responses. We show that a mixture of these codon-optimized ubiquitinated and non-ubiquitinated constructs encoding the same viral envelope protein, glycoprotein D, induced both B and T cell responses, and could protect against lethal viral challenge and reduce ganglionic latency. The optimized vaccines, subcloned into a vector suitable for use in humans, also provided a high level of protection against the establishment of ganglionic latency, an important correlate of HSV reactivation and candidate endpoint for vaccines to proceed to clinical trials.
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Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Herpesvirus Humano 2/imunologia , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Códon , Feminino , Herpes Simples/mortalidade , Herpesvirus Humano 2/genética , Camundongos , Subpopulações de Linfócitos T/imunologia , Ubiquitinação , Vacinas de DNA/administração & dosagem , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genéticaRESUMO
Although hepatitis B surface antigen (HBsAg) per se is highly immunogenic, its use as a vector for the delivery of foreign cytotoxic T-lymphocyte (CTL) epitopes has met with little success because of constraints on HBsAg stability and secretion imposed by the insertion of foreign sequence into critical hydrophobic/amphipathic regions. Using a strategy entailing deletion of DNA encoding HBsAg-specific CTL epitopes and replacement with DNA encoding foreign CTL epitopes, we have derived chimeric HBsAg DNA immunogens which elicited effector and memory CTL responses in vitro, and pathogen- and tumor-protective responses in vivo, when the chimeric HBsAg DNAs were used to immunize mice. We further show that HBsAg DNA recombinant for both respiratory syncytial virus and human papillomavirus CTL epitopes elicited simultaneous responses to both pathogens. These data demonstrate the efficacy of HBsAg DNA as a vector for the delivery of disease-relevant protective CTL responses. They also suggest the applicability of the approach of deriving chimeric HBsAg DNA immunogens simultaneously encoding protective CTL epitopes for multiple diseases. The DNAs we tested formed chimeric HBsAg virus-like particles (VLPs). Thus, our results have implications for the development of vaccination strategies using either chimeric HBsAg DNA or VLP vaccines. HBsAg is the globally administered vaccine for hepatitis B virus infection, inviting its usage as a vector for the delivery of immunogens from other diseases.
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Epitopos de Linfócito T , Antígenos de Superfície da Hepatite B/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas de DNA/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Superfície da Hepatite B/genética , Humanos , Imunização , Memória Imunológica , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírion/fisiologiaRESUMO
Mouse models of orthopoxvirus disease provide great promise for probing basic questions regarding host responses to this group of pathogens, which includes the causative agents of monkeypox and smallpox. However, some essential tools for their study that are taken for granted with other mouse models are not available for these viruses. Here we map and characterize the initial CD8+ T-cell determinants for poxviruses in H-2d-haplotype mice. CD8+ T cells recognizing these three determinants make up around 40% of the total responses to vaccinia virus during and after resolution of infection. We then use these determinants to test if predicted conservation across orthopoxvirus species matches experimental observation and find an unexpectedly cross-reactive variant peptide encoded by ectromelia (mousepox) virus.
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Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Orthopoxvirus/imunologia , Peptídeos/imunologia , Infecções por Poxviridae/imunologia , Animais , Linhagem Celular , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Haplótipos/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Especificidade da EspécieRESUMO
Due to their spatial structure virus-like particles (VLPs) generally induce effective immune responses. VLPs derived from the small envelope protein (HBsAg-S) of hepatitis B virus (HBV) comprise the HBV vaccine. Modified HBsAs-S VLPs, carrying the immunodominant hypervariable region (HVR1) of the hepatitis C virus (HCV) envelope protein E2 within the exposed 'a'-determinant region (HBsAg/HVR1-VLPs), elicited HVR1-specific antibodies in mice. A high percentage of the human population is positive for anti-HBsAg antibodies (anti-HBs), either through vaccination or natural infection. We, therefore, determined if pre-existing anti-HBs could influence immunisation with modified VLPs. Mice were immunised with a commercial HBV vaccine, monitored to ensure an anti-HBs response, then immunised with HBsAg/HVR1-VLPs. The resulting anti-HVR1 antibody titre was similar in mice with or without pre-existing anti-HBs. This suggests that HBsAg/HVR1-VLPs induce a primary immune response to HVR1 in anti-HBs positive mice and, hence, they may be used successfully in individuals already immunised with the HBV vaccine.