Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Randomized, Blinded, Dose-Ranging Trial of an Ebola Virus Glycoprotein Nanoparticle Vaccine With Matrix-M Adjuvant in Healthy Adults.

BACKGROUND: Ebola virus (EBOV) epidemics pose a major public health risk. There currently is no licensed human vaccine against EBOV. The safety and immunogenicity of a recombinant EBOV glycoprotein (GP) nanoparticle vaccine formulated with or without Matrix-M adjuvant were evaluated to support vaccine development. METHODS: A phase 1, placebo-controlled, dose-escalation trial was conducted in 230 healthy adults to evaluate 4 EBOV GP antigen doses as single- or 2-dose regimens with or without adjuvant. Safety and immunogenicity were assessed through 1-year postdosing. RESULTS: All EBOV GP vaccine formulations were well tolerated. Receipt of 2 doses of EBOV GP with adjuvant showed a rapid increase in anti-EBOV GP immunoglobulin G titers with peak titers observed on Day 35 representing 498- to 754-fold increases from baseline; no evidence of an antigen dose response was observed. Serum EBOV-neutralizing and binding antibodies using wild-type Zaire EBOV (ZEBOV) or pseudovirion assays were 3- to 9-fold higher among recipients of 2-dose EBOV GP with adjuvant, compared with placebo on Day 35, which persisted through 1 year. CONCLUSIONS: Ebola virus GP vaccine with Matrix-M adjuvant is well tolerated and elicits a robust and persistent immune response. These data suggest that further development of this candidate vaccine for prevention of EBOV disease is warranted.

A Phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age.

OBJECTIVE: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules. METHODS: Placebo, or vaccine with 60µg or 120µg RSV F protein and 0.2, 0.4, or 0.8mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18-35years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91. RESULTS: All formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120µg RSV F protein and 0.4mg aluminum, but persistence through 91days was modestly (∼25%) superior following two doses of 60µg RSV F protein and 0.8mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p=0.009 overall) over the Day 0 through 90 period. CONCLUSIONS: RSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120µg RSV F and 0.4mg aluminum, which achieved peak immune responses in 14days and sufficient persistence through 91days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686.

Endogenous expression of CD80 co-stimulatory molecule facilitates in vivo tumor regression of oral squamous carcinoma.

BACKGROUND: Most tumor tissues, especially those of non-hematopoietic origin, do not express CD80 co-stimulatory molecules, possibly as a mechanism to evade immune surveillance. The objective of this study was to determine whether abundant endogenous CD80 expression on oral squamous cell carcinoma (SCC) early during tumor progression can facilitate immune elimination and reverse immune tolerance. MATERIALS AND METHODS: The growth of regressor and progressor oral SCC lines with differing endogenous CD80 expression were examined in immune-competent and -deficient mice. Immune effectors were determined by T-cell depletion experiments and immunohistochemistry. RESULTS: Our studies show regression of early tumor growth when immunocompetent animals are inoculated with oral SCC progressor cell lines expressing abundant endogenous CD80. The CD80-induced antitumor response was due largely to induced T-cell responses. CONCLUSION: Our findings suggest that inadequate CD80 expression during early oral SCC formation may contribute to the escape of tumors from immune elimination. This information can be useful in the design of new approaches to generate more effective immunotherapy against this disease.

CD44 interacts with EGFR and promotes head and neck squamous cell carcinoma initiation and progression.

OBJECTIVES: CD44 is a promising target for therapy in head and neck squamous cell carcinoma (HNSCC) and has two defined roles in tumorigenesis: it is a cancer stem cell (CSC) marker and it promotes migration and proliferation through interaction with many signaling molecules. The purpose of this study was to investigate the role of CD44 in HNSCC carcinogenesis. MATERIALS AND METHODS: The effects of CD44 in cell proliferation, migration, apoptosis and cisplatin resistance were studied by its overexpression in HNSCC cells. We also evaluated the effect of CD44 on tumor progression by siRNA methodology, immunohistochemistry (IHC) and western blot analysis. CD44 and EGFR colocalization were examined in CAL 27 cells by laser scanning confocal microscopy. The interaction between CD44 and EGFR was analyzed by immunoprecipation. RESULTS: Overexpression of CD44 enhances cell proliferation and migration and correlates with increased cisplatin resistance and apoptosis inhibition in SCC25 cells. Downregulation of CD44 in CAL27 cells inhibited constitutive EGFR phosphorylation and significantly reduced tumor growth in nude mice. CD44 and EGFR colocalized in CAL 27 cells. CD44 coimmunoprecipated with EGFR in CAL 27 cells, indicating that these proteins interact with each other. CONCLUSION: CD44 therapy in HNSCC may target the CSC population and alter EGFR signaling.

Cytokines IL-1 alpha, IL-6, and GM-CSF constitutively secreted by oral squamous carcinoma induce down-regulation of CD80 costimulatory molecule expression: restoration by interferon gamma.

We previously characterized the expression of CD80 in different murine head and neck squamous cell carcinoma (HNSCC) clones derived following tumor progression in the absence of T cell-mediated immunity in severe combined immunodeficient (SCID) mice. We found that HNSCCs that did not express CD80 grew as progressors, while those that expressed CD80 were regressors when grown in immune-competent animals. In the present study, we characterized expression of a repertoire of immunoregulatory cytokines in these HNSCC lines, and found that HNSCCs that express cytokines IL-1 alpha, IL-6, and GM-CSF do not express CD80, suggesting the hypothesis that these cytokines may down-modulate expression of CD80. Cytokine-conditioned medium from progressor HNSCC and recombinant IL-1 alpha, IL-6, and GM-CSF caused a reduction of CD80 expression in regressor HNSCCs without affecting proliferation. Conversely, the decrease in CD80 expression in progressor HNSCCs could be restored by IFN-gamma, a known inducer of CD80 expression. These data strongly suggest that high levels of cytokines IL-1 alpha, IL-6, and GM-CSF expressed by tumor cells can down-regulate CD80 expression in HNSCC, and that IFN-gamma can independently stimulate expression. These data provide evidence for a novel mechanism of cytokine-mediated down-modulation of CD80 during malignant progression of HNSCC that can be restored by IFN-gamma.