There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused ...by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce ...morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.
The 2017-2018 influenza season reminds us that it is important for health care professionals to be prepared for the annual onslaught of this contagious respiratory disease associated with potentially ...serious complications. Vaccination is by far the best method to prevent and control influenza, reducing illness, hospitalizations, and mortality. The highest rates of influenza-associated morbidity and mortality are observed in older adults. The immune function of older adults decreases with increasing age, a phenomenon termed immunosenescence. Immunosenescence not only confers increased susceptibility to influenza disease, but also renders vaccination less effective. To address the need for improved vaccines that provide enhanced protection to this high-risk group, 2 formulations—a high-dose vaccine and an adjuvanted vaccine—have been approved in recent years specifically for people aged 65 years and over. Here we discuss: the challenges of influenza immunization in those 65 years and older; the recent advancements in vaccines targeted at this age group; and the latest influenza vaccine recommendations for the 2017-2018 influenza season in the United States.
Cholera remains a problem in developing countries and a risk for travelers. Hypochlorhydria, blood group O, cardiac and renal disease increase the risk of developing cholera gravis. Oral vaccines ...containing inactivated Vibrio cholerae and requiring two doses are available in some countries. No cholera vaccine had been available for U.S. travelers for decades until 2016 when CVD 103-HgR (VAXCHORA™), an oral live attenuated vaccine, was licensed by the U.S. FDA. Areas covered: Enduring protection following wild-type cholera provided the rationale to develop a single-dose live oral vaccine. CVD 103-HgR is well-tolerated and protects against cholera caused by V. cholerae O1 of either serotype (Inaba, Ogawa) and biotype (El Tor, Classical). Since 90% vaccine efficacy is evident 10 days post-ingestion of a single dose, CVD 103-HgR can rapidly protect travelers. Vibriocidal antibody seroconversion correlates with protection; >90% of U.S. adult (including elderly) vaccinees seroconvert. The U.S. Public Health Service's Advisory Committee on Immunization Practices recommends CVD 103-HgR for U.S. travelers to areas of ongoing cholera transmission. Expert commentary: Next steps include evaluations in children, post-licensure safety and effectiveness monitoring, diminishing cold chain constraints, optimizing a 'high-dose' formulation for developing countries, and diminishing/eliminating the need for water to administer a dose.
Successful vaccination of the elderly against important infectious pathogens that cause high morbidity and mortality represents a growing public health priority. Building on the theme of aging and ...immunosenescence, we review mechanisms of human immunosenescence and the immune response to currently licensed vaccines. We discuss the difficulties in identifying the risk factors that, in addition to aging, cause immunosenescence and address the relative paucity of vaccine studies in the elderly. We conclude that vaccine responses are blunted in the elderly compared with that of healthy young adults. However, it is also clear that our understanding of the mechanisms underlying immunosenescence is limited and much remains to be learned to improve the effectiveness of next generation vaccines.
Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection.
We conducted a randomized, double-blind, placebo-controlled, ...multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms.
Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus-specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05).
This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.).
Catastrophic damage and floods followed the deadliest cyclone on record for the Southern Hemisphere. In the aftermath of Cyclone Idai, a cholera outbreak was detected. The global stockpile of oral ...cholera vaccine was rapidly deployed to counter this fast-growing epidemic. We urge the international community to continue to highlight the importance of water, sanitation, and hygiene as the long-term goal for controlling cholera and meeting the 2030 Sustainable Development Goals.
No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect ...short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model.
Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units CFU) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration.
The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001).
The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine.
NCT01895855.
Background. Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide. Methods.We conducted 2 phase 1 double-blind, controlled studies of a ...virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18–49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50-and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors. Results. The most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8-and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50-or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues. Conclusions. The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study. Trial Registration. ClinicalTrials.gov identifier: NCT00806962.
Background. Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent ...intramuscular norovirus virus-like particle (VLP) vaccine. Methods. Forty-eight adults aged 18-49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII. 4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18-49 (n = 16), 50-64 (n = 19), and 65-85 (n = 19) years, received 2 doses of vaccine containing 50 (µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose. Results. Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII. 4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18-49,50-64, and 65-83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of > 200. Conclusions. The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks.
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