A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose

IntroductionAcute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population.MethodsIn this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18–49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 μg GI.1 and 50 μg GII.4c VLP antigens and 500 μg Al(OH)₃, with or without 15 μg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection.ResultsAfter one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18–49, 60–74, 75–84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue.ConclusionsAdults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.     

Dissection of seroreactivity against the tryptophan-rich motif of the feline immunodeficiency virus transmembrane glycoprotein

Immunogenicity of the tryptophan-rich motif (TrpM) in the membrane-proximal ectodomain of the transmembrane (TM) glycoprotein of feline immunodeficiency virus (FIV) was investigated. Peptide 59, a peptide containing the TrpM of the TM of FIV, was covalently coupled to Qbeta phage virus-like particles (Qbeta-59) in the attempt to induce potent anti-TrpM B cell responses in cats. All Qbeta-59 immunized cats, but not cats that received a mixture of uncoupled Qbeta and peptide 59, developed antibodies that reacted with a same epitope in extensive binding and binding competition assays. The epitope recognized was composed of three amino acids, two of which are adjacent. However, Qbeta-59-immune sera failed to recognize whole FIV in all binding and neutralization assays performed. Furthermore, no reactivity against the TrpM was detected by screening sera from FIV-infected cats that had reacted with TM peptides, confirming that this epitope does not seem to be serologically functional in the FIV virion. The data suggest that TrpM may not be a suitable target for antiviral vaccine design.     

Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n= 169) and CIN 3 (n= 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P= 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.     

Immunogenicity and performance of an enterovirus 71 virus-like-particle vaccine in nonhuman primates

A vaccine against human enterovirus 71 (EV-A71) is urgently needed to combat outbreaks of EV-A71 and in particular, the serious neurological complications that manifest during these outbreaks. In this study, an EV-A71 virus-like-particle (VLP) based on a B5 subgenogroup (EV-A71-B5 VLP) was generated using an insect cell/baculovirus platform. Biochemical analysis demonstrated that the purified VLP had a highly native procapsid structure and initial studies in vivo demonstrated that the VLPs were immunogenic in mice. The impact of VLP immunization on infection was examined in non-human primates using a VLP prime-boost strategy prior to EV-A71 challenge. Rhesus macaques were immunized on day 0 and day 21 with VLPs (100 μg/dose) containing adjuvant or with adjuvant alone (controls), and were challenged with EV-A71 on day 42. Complete blood counts, serum chemistry, magnetic resonance imaging (MRI) scans, and histopathology results were mostly normal in vaccinated and control animals after virus challenge demonstrating that the fatal EV-A71-B3 clinical isolate used in this study was not highly virulent in rhesus macaques. Viral genome and/or infectious virus were detected in blood, spleen or brain of two of three control animals, but not in any specimens from the vaccinated animals, indicating that VLP immunization prevented systemic spread of EV-A71 in rhesus macaques. High levels of IgM and IgG were detected in VLP-vaccinated animals and these responses were highly specific for EV-A71 particles and capsid proteins. Serum from vaccinated animals also exhibited similar neutralizing activity against different subgenogroups of EV-A71 demonstrating that the VLPs induced cross-neutralizing antibodies. In conclusion, our EV-A71-B5 VLP is safe, highly immunogenic, and prevents systemic EV-A71-B3 infection in nonhuman primates making it a viable attractive vaccine candidate for EV-A71.     

Overview of high-risk HPV's 16 and 18 infected cervical cancer: Pathogenesis to prevention

As general, the Human papillomavirus (HPV) causes the most sexually transmitted diseases. Among well categorized 80 types, the high-risk types HPV's 16 and 18 are highly involved in 70% of cervical cancer. The virulence of HPV is mainly exhibited by E5, E6 and E7 encoded oncoproteins that cause low to high-grade cervical lesions (CIN-1, 2, 3), leading to form 99.7% of squamous cell and 89% of adenocarcinomas cervical cancer worldwide. This study mainly encircles the major role of E5, E6 and E7 oncoproteins in HPV 16 and 18. Further discussed the uprising of significant biomarkers and their cellular process in different stages of cervical cancer with current prevention and treatment regimens. Hence, this integration will evoke novel markers, potential vaccination and various treatments approaches with special reference for HPV16 and 18 infected cervical cancers.     

Serologic response to human oncogenic papillomavirus types 16, 18, 31, 33, 39, 58 and 59 virus-like particles in colombian women with invasive cervical cancer

The serologic response against virus-like particles (VLP) from 7 high risk genital papillomaviruses was investigated by ELISA in 147 Colombian women with invasive cervical cancer and 147 age-matched cytologically normal and HPV-DNA negative women. Anti-VLP antibodies were detected in 82% of the invasive cervical cancer patients and in 56% of the controls. Detection of antibodies against multiple HPV types is the rule and the presence of high antibody titers was associated with higher survival of cancer patients. Higher anti-VLP seroprevalence was observed in younger cancer patients. In those followed serologically for 1 year, antibodies generally remained at the same level. However, in some patients an increase or decrease in antibody levels occurred simultaneously for multiple HPV types, suggesting cross-reactivity between the HPV types investigated. Investigation of seroreactivity between 8 high risk HPVs suggested that there is some cross-reactivity between phylogeneticaly-related types such as 16, 31, 33 and 58; and 18, 45 and 59. In conclusion, our results confirmed (i) the high rate of HPV infections in Colombia, both in patients with cervical cancer and in the general population, and the particularly high rate of infections due to HPV 31 and 58; and (ii) the validity of anti-VLPs as a marker of present or past HPV infection. The simultaneous appearance or disappearance of antibodies against multiple HPV VLPs suggests that the antibodies detected by ELISA are not always type specific.     

心室晚电位(VLP)阳性与左室射血分数(EF)降低对心肌梗死心性猝死相关性的研究

目的　探讨心室晚电位、左室射血分数在降低心梗性猝死的关系。方法　采用时域定量分析法(SA -ECG) ,首选 12导联心电图、心向量图、测定VLP波叠加多次后清除数 ;测定左室射血分数。结果　EF <4 0 % ,VLP >4 0 %时 ,心猝死发生率极高。结论　VLP与EF在判断心肌梗死性猝死中意义较大     

老年冠心病患者心室晚电位随访观察

对52例VLP阳性和可疑阳性及20例VLP阴性的老年冠心病患者进行了3年8个月追踪观察。冠心病心绞痛组VLP阳性者24例,转为阴性者8例(33.0％);心肌梗塞组VLP阳性者28例,转为阴性者7例(29.1％)。两组伴有室性心律失常14例,其中4例发生持续性室速,室颤死亡,2例心脏突然骤停猝死。20例VLP阴性者无1例发生室速及猝死。本文初步研究表明VLP阳性对预测冠心病患者室速、室颤及猝死的发生有一定的临床意义。     

Epitope selection and their placement for increased virus neutralization in a novel vaccination strategy for porcine epidemic diarrhea virus utilizing the Hepatitis B virus core antigen

Porcine epidemic diarrhea virus (PEDV) is a member of the Alphacoronaviridae genus within the Coronaviridae family. It is the causative agent of porcine epidemic diarrhea, a disease that can have mortality rates as high as 100% in suckling piglets. PEDV causes severe economic loss, and has been in existence for decades. A panzootic starting in 2010 renewed interest in the development of a universal vaccine toward PEDV. This report details several design changes made to a Hepatitis B virus core antigen (HBcAg)-based recombinant vaccine strategy, and their effect in vivo. Initially, several multi-antigen vaccine candidates were able to elicit antibodies specific to three out of four B-cell epitopes inserted into the chimeric proteins. However, a lack of virus neutralization led to a redesign of the vaccines. The focus of the newly redesigned vaccines was to elicit a strong immune response to the YSNIGVCK amino acid motif from PEDV. Genetically modified new vaccine candidates were able to elicit a strong antibody (Ab) response to the YSNIGVCK epitope, which correlated with an increased ability to neutralize the CO strain of PEDV. Additionally, the location of the inserted PEDV epitopes within the vector protein was shown to affect the immune recognition toward the native HBcAg during vaccination.