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SeVRSV is a replication-competent Sendai virus (SeV)-based vaccine carrying the respiratory syncytial virus (RSV) fusion protein (F) gene. Unmanipulated, non-recombinant SeV is a murine parainfluenza virus type 1 (PIV-1) and serves as a Jennerian vaccine for human PIV-1 (hPIV-1). SeV protects African green monkeys (AGM) from infection after hPIV-1 challenge. The recombinant SeVRSV additionally targets RSV and protects AGM from lower respiratory infections after RSV challenge. The present study is the first to report on the safety, viral genome detection, and immunogenicity following SeVRSV vaccination of healthy adults. Seventeen and four healthy adults received intranasal SeVRSV and PBS, respectively, followed by six months of safety monitoring. Virus genome (in nasal wash) and vaccine-specific antibodies (in sera) were monitored for two and four weeks, respectively, post-vaccination. The vaccine was well-tolerated with only mild to moderate reactions that were also present in the placebo group. No severe reactions occurred. As expected, due to preexisting immunity toward hPIV-1 and RSV in adults, vaccine genome detection was transient. There were minimal antibody responses to SeV and negligible responses to RSV F. Results encourage further studies of SeVRSV with progression toward a clinical trial in seronegative children. Abbreviations: AE-adverse event; SAE-serious adverse event; SeV-Sendai virus; RSV-respiratory syncytial virus; PIV-1-parainfluenza virus-type 1; hPIV-1-human parainfluenza virus-type 1; F-RSV fusion protein; SeVRSV-recombinant SeV carrying the RSV F gene; Ab-antibody; MSW-medically significant wheezing; NOCMC-new onset chronic medical condition, mITT-modified Intent to Treat; ALRI-acute lower respiratory tract infection.

Summary Background (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. Methods The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18–55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov ( NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). Findings In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0–∞) of 13 000 μg × h/L (median AUC0–∞ 24 283 [IQR 16 135–31 311] μg × h/L, median terminal half-life 17·4 h [IQR 16·1–24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6–1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10 PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0–2·5) and 6·47 h (95% CI 5·88–7·18) for 150 mg, and 4·1 (3·7–4·4) and 3·56 h (3·29–3·88) for 600 mg. Interpretation The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. Funding Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.

Human parainfluenza virus type 1 (hPIV-1) is the most common cause of laryngotracheobronchitis (croup), resulting in tens of thousands of hospitalizations each year in the United States alone. No licensed vaccine is yet available. We have developed murine PIV-1 (Sendai virus [SeV]) as a live Jennerian vaccine for hPIV-1. Here, we describe vaccine testing in healthy 3- to 6-year-old hPIV-1-seropositive children in a dose escalation study. One dose of the vaccine (5 × 105, 5 × 106, or 5 × 10750% egg infectious doses) was delivered by the intranasal route to each study participant. The vaccine was well tolerated by all the study participants. There was no sign of vaccine virus replication in the airway in any participant. Most children exhibited an increase in antibody binding and neutralizing responses toward hPIV-1 within 4 weeks from the time of vaccination. In several children, antibody responses remained above incoming levels for at least 6 months after vaccination. Data suggest that SeV may provide a benefit to 3- to 6-year-old children, even when vaccine recipients have preexisting cross-reactive antibodies due to previous exposures to hPIV-1. Results encourage the testing of SeV administration in young seronegative children to protect against the serious respiratory tract diseases caused by hPIV-1 infections.

In the influenza virus field, antibody reagents from research animals have been instrumental in the characterization of antigenically distinct hemagglutinin and neuraminidase membrane molecules. These small animal reagents continue to support the selection of components for inclusion in human influenza virus vaccines. Other cocktail vaccines against variant pathogens (e.g., polio virus, pneumococcus) are similarly designed to represent variant antigens, as defined by antibody reactivity patterns. However, a vaccine cocktail comprising diverse viral membrane antigens defined in this way has not yet been advanced to a clinical efficacy study in the HIV-1 field. In this study, we describe the preparation of mouse antibodies specific for HIV-1 gp140 or gp120 envelope molecules. Our experiments generated renewable reagents able to discriminate HIV-1 envelopes from one another. Monoclonals yielded more precise discriminatory capacity against their respective immunogens than did a small panel of polyclonal human sera derived from recently HIV-1-infected patients. Perhaps these and other antibody reagents will ultimately support high-throughput cartography studies with which antigenically-distinct envelope immunogens may be formulated into a successful HIV-1 envelope cocktail vaccine.

Background The world is facing a novel H1N1 pandemic. A pandemic scare with a similar virus in 1976 resulted in the vaccination of nearly 45 million persons. We hypothesized that prior receipt of the 1976 “swine flu” vaccine would enhance immune responses to the 2009 novel H1N1 strain.

The human immune system has evolved to recognize antigenic diversity, a strength that has been harnessed by vaccine developers to combat numerous pathogens (e.g., pneumococcus, influenza virus, rotavirus). In each case, vaccine cocktails were formulated to include antigenic variants of the target. To combat HIV-1 diversity, we assembled a cocktail vaccine comprising dozens of envelopes, delivered as recombinant DNA, vaccinia virus, and protein for testing in a clinical trial. One vaccinee has now completed vaccinations with no serious adverse events. Preliminary analyses demonstrate early proof-of-principle that a multi-envelope vaccine can elicit neutralizing antibody responses toward heterologous HIV-1 in humans.

The St. Jude Children's Research Hospital (St. Jude) HIV-1 vaccine program is based on the observation that multiple antigenically distinct HIV-1 envelope protein structures are capable of mediating HIV-1 infection. A cocktail vaccine comprising representatives of these diverse structures (immunotypes) is therefore considered necessary to elicit lymphocyte populations that prevent HIV-1 infection. This strategy is reminiscent of that used to design a currently licensed and successful 23-valent pneumococcus vaccine. Three recombinant vector systems are used for the delivery of envelope cocktails (DNA, vaccinia virus, and purified protein), and each of these has been tested individually in phase I safety trials. A fourth FDA-approved clinical trial, in which diverse envelopes and vectors are combined in a prime-boost vaccination regimen, has recently begun. This trial will continue to test the hypothesis that a multi-vector, multi-envelope vaccine can elicit diverse B- and T-cell populations that can prevent HIV-1 infections in humans.

Treatment of Lewis rats with a single dose of OX19 antibody, specific for rat CD5, uniformly prevented the development of experimental autoimmune encephalomyelitis (EAE). This protective effect had several notable characteristics: (1) it persisted for at least 10 days; (2) it could be achieved with either high doses of the antibody (200 micrograms) or lower doses (100-200 micrograms), which did not deplete T cell populations; and (3) the treated animals were able to mount comparable T cell responses to both myelin basic protein and myelin-unrelated antigens. In addition, antibody treatment consistently prevented the development of adoptively transferred EAE, suggesting that enhanced suppressor cell activity may have contributed to the protection. Antibodies such as OX19 appear capable of blocking the development of EAE, and perhaps other autoimmune diseases as well.

To combat HIV-1 diversity we are developing a multienvelope vaccine (comprising DNA vaccinia virus and protein vectors). Toward this goal we conducted a phase I clinical trial of EnvPro a gp140 protein formulated in alum. The vaccine was well tolerated and elicited an immune response in every trial participant. (authors)

Human parainfluenza viruses are responsible for tens of thousands of hospitalizations and hundreds of thousands of emergency room visits each year in the United States. Included in this group of viruses is human parainfluenza virus-type 1 (hPIV-1), the main causative agent of laryngotracheobronchitis (croup) in young children, for which there is currently no licensed vaccine. In response to this need, we have developed a Jennerian vaccine that employs the use of murine PIV-1 (Sendai virus, SeV) to produce cross-reactive antibodies towards hPIV-1. The vaccine was administered as a single intranasal dose to healthy, hPIV-1 seropositive, 3-6 year old children in a dose escalation study (5 x 105, 5 x 106 or 5 x 107 EID50). Importantly, the vaccine was well tolerated by all participants. No replication of the viral vaccine was detected in the airway of any participant. Within four weeks of vaccination, most participants showed an increase in binding and neutralizing antibodies towards hPIV-1. For several participants, antibody responses remained elevated at six months post-vaccination. The results of this study suggest that hPIV-1 vaccination may be beneficial to boost immunity in seropositive children, and encourage testing of the vaccine in young, seronegative children who are most at risk for respiratory virus disease.

The recall of CD8+T-cell memory established by infectingH-2bmice with an H1N1 influenza A virus provided a measure of protection against an extremely virulent H7N7 virus. The numbers of CD8+effector and memory T cells specific for the shared, immunodominant DbNP366epitope were greatly increased subsequent to the H7N7 challenge, and though lung titers remained as high as those in naive controls for 5 days or more, the virus was cleared more rapidly. Expanding the CD8+memory T-cell pool (10%) by sequential priming with two different influenza A viruses (H3N2→H1N1) gave much better protection. Though the H7N7 virus initially grew to equivalent titers in the lungs of naive and double-primed mice, the replicative phase was substantially controlled within 3 days. This tertiary H7N7 challenge caused little increase in the magnitude of the CD8+DbNP366+T-cell pool, and only a portion of the memory population in the lymphoid tissue could be shown to proliferate. The great majority of the CD8+DbNP366+set that localized to the infected respiratory tract had, however, cycled at least once, though recent cell division was shown not to be a prerequisite for T-cell extravasation. The selective induction of CD8+T-cell memory can thus greatly limit the damage caused by a virulent influenza A virus, with the extent of protection being directly related to the number of available responders. Furthermore, a large pool of CD8+memory T cells may be only partially utilized to deal with a potentially lethal influenza infection.

Optimal expansion of influenza virus nucleoprotein (DbNP366)-specific CD8+T cells following respiratory challenge of naive Ig−/−μMT mice was found to require CD4+T-cell help, and this effect was also observed in primed animals. Absence of the CD4+population was consistently correlated with diminished recruitment of virus-specific CD8+T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8+set generated during the recall response in Ig−/−mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4+T-cell response. Both the magnitude and the localization profiles of virus-specific CD8+T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4+T cells.

Viridans streptococci are an important cause of bacteremia and septic shock in neutropenic patients, especially patients receiving chemotherapeutic agents that induce severe mucositis. The mechanisms by which viridans streptococci cause septic shock are unclear. We hypothesized that septic shock due to viridans streptococci is attributable to host cytokine production. Three clinical isolates of viridans streptococci were evaluated for their ability to induce production of tumor necrosis factor-alpha (TNF-alpha) by RAW 264.7 murine macrophages. These three strains of viridans streptococci induced TNF-alpha in a dose-dependent fashion, and the kinetics of TNF-alpha induction were similar to those observed with a clinical isolate of Escherichia coli.