Ethics of a partially effective dengue vaccine: Lessons from the Philippines.

Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine developed by SanofiPasteur is widely licensed in dengue-endemic countries. In a large cohort study Dengvaxia was found to partially protect children who had prior dengue virus (DENV) infections but sensitized seronegative children to breakthrough DENV disease of enhanced severity. In 2019, the European Medicines Agency and the US FDA issued licenses that reconciled safety issues by restricting vaccine to individuals with prior dengue infections. Using revised Dengvaxia efficacy and safety data we sought to estimate hospitalized and severe dengue cases among the more than 800,000 9 year-old children vaccinated in the Philippines. Despite an overall vaccine efficacy of 69% during 4 years post-vaccination we project there will be more than one thousand vaccinated seronegative and seropositive children hospitalized for severe dengue. Assisting these children through a program of enhanced surveillance leading to improved care deserves widespread support. Clinical responses observed during breakthrough dengue infections in vaccinated individuals counsel prudence in design of vaccine policies. Recommendations concerning continued use of this dengue vaccine are: (1) obtain a better definition of vaccine efficacy and safety through enhanced phase 4 surveillance, (2) obtain a valid, accessible, sensitive, specific and affordable serological test that identifies past wild-type dengue virus infection and (3) clarify safety and efficacy of Dengvaxia in flavivirus immunes. In the absence of an acceptable serological screening test these unresolved ethical issues suggest Dengvaxia be given only to those signing informed consent.

Protective and immunological behavior of chimeric yellow fever dengue vaccine.

Clinical observations from the third year of the Sanofi Pasteur chimeric yellow fever dengue tetravalent vaccine (CYD) trials document both protection and vaccination-enhanced dengue disease among vaccine recipients. Children who were 5 years-old or younger when vaccinated experienced a DENV disease resulting in hospitalization at 5 times the rate of controls. On closer inspection, hospitalized cases among vaccinated seropositives, those at highest risk to hospitalized disease accompanying a dengue virus (DENV) infection, were greatly reduced by vaccination. But, seronegative individuals of all ages after being vaccinated were only modestly protected from mild to moderate disease throughout the entire observation period despite developing neutralizing antibodies at high rates. Applying a simple epidemiological model to the data, vaccinated seronegative individuals of all ages were at increased risk of developing hospitalized disease during a subsequent wild type DENV infection. The etiology of disease in placebo and vaccinated children resulting in hospitalization during a DENV infection, while clinically similar are of different origin. The implications of the observed mixture of DENV protection and enhanced disease in CYD vaccinees are discussed.

The Human Hookworm Vaccine.

Hookworm infection is one of the world's most common neglected tropical diseases and a leading cause of iron deficiency anemia in low- and middle-income countries. A Human Hookworm Vaccine is currently being developed by the Sabin Vaccine Institute and is in phase 1 clinical testing. The candidate vaccine is comprised of two recombinant antigens known as Na-GST-1 and Na-APR-1, each of which is an important parasite enzyme required for hookworms to successfully utilize host blood as a source of energy. The recombinant proteins are formulated on Alhydrogel(®) and are being tested in combination with a synthetic Toll-like receptor 4 agonist. The aim of the vaccine is to induce anti-enzyme antibodies that will reduce both host blood loss and the number of hookworms attached to the gut. Transfer of the manufacturing technology to the Oswaldo Cruz Foundation (FIOCRUZ)/Bio-Manguinhos (a Brazilian public sector developing country vaccine manufacturer) is planned, with a clinical development plan that could lead to registration of the vaccine in Brazil. The vaccine would also need to be introduced in the poorest regions of Africa and Asia, where hookworm infection is highly endemic. Ultimately, the vaccine could become an essential tool for achieving hookworm control and elimination, a key target in the 2012 London Declaration on Neglected Tropical Diseases.

U.S. medical countermeasure development since 2001: a long way yet to go.

The U.S. government has taken significant steps toward developing and acquiring vaccines, drugs, and other medical countermeasures (MCMs) to protect and treat the population after a biological attack. In contrast to 2001, there is now a procedure for the Department of Health and Human Services (HHS) to develop, license, and stockpile MCMs for civilian use. Another major accomplishment is smallpox preparedness: There is now an adequate supply of vaccine for every person in the U.S., and there is an alternative vaccine meant for immunocompromised people and those with close contact with them. In spite of these and other accomplishments, the U.S. government MCM effort has been criticized by federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts who state that the efforts lack central leadership and accountability and that the pace of progress has been slow. A clear operational strategy for using MCMs, which would guide their development and acquisition, is also lacking. In this article, we review key areas of progress made since 2001 to develop and acquire MCMs, and we summarize what we judge to be the most critical and often mentioned areas where improvements are needed.

Project BioShield: what it is, why it is needed, and its accomplishments so far.

Project BioShield is a comprehensive effort involving the US Department of Health and Human Services (HHS), its component agencies, and other partner federal agencies to speed the research, development, acquisition, and availability of medical countermeasures to improve the government's preparedness for and ability to counter chemical, biological, radiological, and nuclear threat agents. The legislation authorizes use of the Special Reserve Fund, which makes available $5.6 billion over 10 years for the advanced development and purchase of medical countermeasures. This appropriation is intended to provide an economic incentive to the pharmaceutical industry to develop medical countermeasures for which the government is the only significant market. Acquisitions under Project BioShield are restricted to products in development that are potentially licensable within 8 years from the time of contract award. In exercising the procurement authorities under Project BioShield, HHS has launched acquisition programs to address each of the 4 threat agents, including Bacillus anthracis (anthrax), smallpox virus, botulinum toxins, and radiological/nuclear agents, originally deemed by the Department of Homeland Security to be threats to the US population sufficient to affect national security. At the time of writing, 7 contracts have been awarded: (1) recombinant protective antigen anthrax vaccine, the next-generation anthrax vaccine (contract terminated in December 2006 for default); (2) anthrax vaccine adsorbed, the currently licensed anthrax vaccine; (3) anthrax therapeutics (monoclonal); (4) anthrax therapeutics (human immune globulin); (5) the pediatric formulation of potassium iodide; (6) Ca- and Zn-diethylenetriaminepentaacetate (DTPA), chelating agents to treat ingestion of certain radiological particles; and (7) botulinum antitoxins. Additional acquisition contracts are expected to be awarded in 2007.

Swine influenza a outbreak, Fort Dix, New Jersey, 1976.

In early 1976, the novel A/New Jersey/76 (Hsw1N1) influenza virus caused severe respiratory illness in 13 soldiers with 1 death at Fort Dix, New Jersey. Since A/New Jersey was similar to the 1918-1919 pandemic virus, rapid outbreak assessment and enhanced surveillance were initiated. A/New Jersey virus was detected only from January 19 to February 9 and did not spread beyond Fort Dix. A/Victoria/75 (H3N2) spread simultaneously, also caused illness, and persisted until March. Up to 230 soldiers were infected with the A/New Jersey virus. Rapid recognition of A/New Jersey, swift outbreak assessment, and enhanced surveillance resulted from excellent collaboration between Fort Dix, New Jersey Department of Health, Walter Reed Army Institute of Research, and Center for Disease Control personnel. Despite efforts to define the events at Fort Dix, many questions remain unanswered, including the following: Where did A/New Jersey come from? Why did transmission stop?

Effect of vaccination with a recombinant fusion protein encoding an astacinlike metalloprotease (MTP-1) secreted by host-stimulated Ancylostoma caninum third-stage infective larvae.

Laboratory dogs were vaccinated intramuscularly with a recombinant fusion protein (expressed and isolated from Escherichia coli) formulated with the Glaxo SmithKline Adjuvant System 02 (AS02). The fusion protein encoded Ac-MTP-1, a developmentally regulated astacinlike metalloprotease secreted by host-stimulated Ancylostoma caninum third-stage larvae (L3). Control dogs were injected intramuscularly with an equivalent amount of AS02 adjuvant alone. The vaccinated and control dogs were then challenged by s.c. injection of 500 L3 of the canine hookworm A. caninum. The vaccinated dogs developed prechallenge immunoglobulin G2 (IgG2) antibody responses specific to anti-Ac-MTP-1-fusion protein with titers ranging between 1:40,000 and 1:364,000, whereas they developed antigen-specific immunoglobulin E antibody responses with titers ranging between 1:500 and 1:1,500. By immunoblotting, canine sera obtained from the vaccinated dogs recognized a protein of the estimated apparent molecular weight of Ac-MTP-1 in activated L3 secretory products. Spearman rank order correlations between the canine intestinal adult hookworm burden and quantitative egg counts at necropsy and anti-Ac-MTP-1 IgG2 antibody titers revealed a statistically significant inverse association (r = -0.89; P = 0.04), suggesting that this molecule offers promise as a recombinant vaccine.

Progress in the development of a recombinant vaccine for human hookworm disease: the Human Hookworm Vaccine Initiative.

Hookworm infection is one of the most important parasitic infections of humans, possibly outranked only by malaria as a cause of misery and suffering. An estimated 1.2 billion people are infected with hookworm in areas of rural poverty in the tropics and subtropics. Epidemiological data collected in China, Southeast Asia and Brazil indicate that, unlike other soil-transmitted helminth infections, the highest hookworm burdens typically occur in adult populations, including the elderly. Emerging data on the host cellular immune responses of chronically infected populations suggest that hookworms induce a state of host anergy and immune hyporesponsiveness. These features account for the high rates of hookworm reinfection following treatment with anthelminthic drugs and therefore, the failure of anthelminthics to control hookworm. Despite the inability of the human host to develop naturally acquired immune responses to hookworm, there is evidence for the feasibility of developing a vaccine based on the successes of immunising laboratory animals with either attenuated larval vaccines or antigens extracted from the alimentary canal of adult blood-feeding stages. The major antigens associated with each of these larval and adult hookworm vaccines have been cloned and expressed in prokaryotic and eukaryotic systems. However, only eukaryotic expression systems (e.g., yeast, baculovirus, and insect cells) produce recombinant proteins that immunologically resemble the corresponding native antigens. A challenge for vaccinologists is to formulate selected eukaryotic antigens with appropriate adjuvants in order to elicit high antibody titres. In some cases, antigen-specific IgE responses are required to mediate protection. Another challenge will be to produce anti-hookworm vaccine antigens at high yield low cost suitable for immunising large impoverished populations living in the developing nations of the tropics.

Effect of vaccinations with recombinant fusion proteins on Ancylostoma caninum habitat selection in the canine intestine.

Laboratory dogs were vaccinated subcutaneously with 3 different recombinant fusion proteins, each precipitated with alum or calcium phosphate. The vaccinated dogs were then challenged orally with 400 third-stage infective larvae (L3) of the canine hookworm, Ancylostoma caninum. The 3 A. caninum antigens selected were Ac-TMP, an adult-specific secreted tissue inhibitor of metalloproteases; Ac-AP, an adult-specific secreted factor Xa serine protease inhibitor anticoagulant; and Ac-ARR-1, a cathepsin D-like aspartic protease. Each of the 3 groups comprised 6 male beagles (8 +/- 1 wk of age). A fourth group comprised control dogs injected with alum. All of the dogs vaccinated with Ac-TMP or Ac-APR-1 exhibited a vigorous antigen-specific antibody response, whereas only a single dog vaccinated with Ac-AP developed an antibody response. Dogs with circulating antibody responses exhibited 4.5-18% reduction in the numbers of adult hookworms recovered from the small intestines at necropsy, relative to alum-injected dogs. In contrast, there was a concomitant increase in the number of adult hookworms recovered from the colon. The increase in colonic hookworms was as high as 500%, relative to alum-injected dogs. Female adult hookworms were more likely to migrate into the colon than were males. Anti-enzyme and anti-enzyme inhibitor antibodies correlated with an alteration in adult hookworm habitat selection in the canine gastroinntestinal tract.

Anthrax as a biological weapon, 2002: updated recommendations for management.

OBJECTIVE: To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population. PARTICIPANTS: The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public health, and emergency management institutions and agencies. EVIDENCE: MEDLINE databases were searched from January 1966 to January 2002, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Reference review identified work published before 1966. Participants identified unpublished sources. CONSENSUS PROCESS: The first draft synthesized the gathered information. Written comments were incorporated into subsequent drafts. The final statement incorporated all relevant evidence from the search along with consensus recommendations. CONCLUSIONS: Specific recommendations include diagnosis of anthrax infection, indications for vaccination, therapy, postexposure prophylaxis, decontamination of the environment, and suggested research. This revised consensus statement presents new information based on the analysis of the anthrax attacks of 2001, including developments in the investigation of the anthrax attacks of 2001; important symptoms, signs, and laboratory studies; new diagnostic clues that may help future recognition of this disease; current anthrax vaccine information; updated antibiotic therapeutic considerations; and judgments about environmental surveillance and decontamination.

Comparison of dengue-2 and dengue-3 virus strains by neutralization tests and identification of a subtype of dengue-3

Strains of dengue-2 and dengue-3 viruses of diverse geographic origins including southeast Asia, the Caribbean region, and Tahati were compared by plaque-reduction neutralisation tests with hyperimmune-mouse asctic fluids and human convalescent sera. The dengue-2 strains all appeared similar. The dengue-3 strains from the Caribbean and from Tahiti were similar to each other and differed significantly from the southeast Asian strains. A subtype of dengue-3 was defined (AU)