Funding for malaria genome sequencing.
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Animals↗
Biomedical subjects
W H Bancroft
Publications and source records attributed to W H Bancroft.
Non-A, non-B hepatitis and antibody to hepatitis C virus.
Stored serum samples from the Transfusion-transmitted Viruses Study in the 1970s were tested for the presence of antibody to hepatitis C virus (anti-HCV). Single specimens from five control subjects who did not receive transfusions tested negative for anti-HCV. Of four control subjects who did not receive transfusions and who developed non-A, non-B (NANB) hepatitis after hospitalization, three remained anti-HCV negative; the fourth person with postoperative NANB hepatitis tested anti-HCV positive before the operation. Five transfusion recipients with posttransfusion hepatitis B virus infection remained seronegative; a sixth with NANB hepatitis as well as hepatitis B virus infection had seroconversion for anti-HCV. Five of nine transfusion recipients with NANB hepatitis had anti-HCV seroconversion. These results show that present anti-HCV testing demonstrates an etiologic basis for approximately half of the cases of transfusion-associated NANB hepatitis, particularly those that develop chronicity. Although cases of NANB hepatitis without seroconversion may be explained otherwise, they may be caused by another, presently unidentified, virus.
Blood Transfusion↗
The military and hepatitis B.
Hepatitis B virus (HBV) is an important cause of morbidity in military forces. HBV threatens a safe blood supply for mass casualties, contributes to rising health care costs and presents an occupational risk to health care workers. The susceptibility of soldiers reflects that of other residents of their country of origin. In intermediate and high-prevalence regions, infections usually occur in young adults and follow exposure to an HBV carrier through blood or sexual contact. Control of HBV infections must rely on education regarding risk factors, screening of blood donors and immunization. Military populations provide unique opportunities for studying the epidemiology of hepatitis B and carrying out mass vaccination programmes.
Hepatitis B↗
Preparation of an attenuated dengue 4 (341750 Carib) virus vaccine. II. Safety and immunogenicity in humans.
To determine safety and immunogenicity, a single 0.5 ml dose of a monovalent live-attenuated dengue (DEN) 4 (341750 Carib) vaccine was given sc to 3 groups of flavivirus nonimmune volunteers in increasing concentrations. Two recipients received 10(3) plaque forming units (PFU)/dose (1:100 dilution of stock vaccine). One remained asymptomatic, but became viremic between days 12 and 15, experienced a mild elevation of temperature (37.4 degrees C), and developed DEN-4 specific antibody. Neither recipient of the 10(4) PFU became infected. Eight volunteers then received undiluted vaccine (10(5) PFU). Viremia and antibody (neutralizing, hemagglutination inhibition, and IgM) developed in 5 of the 8 (63%). These 5 volunteers also developed a scarcely noticeable macular, blanching rash and minimal temperature elevations (37.3, 38.1, 37, 37.9, and 37.9 degrees C). Clinically insignificant decreases in total white blood cell, lymphocyte, and polymorphonuclear cell counts and an elevation in mononuclear cell counts occurred in association with viremia. This vaccine is safe, reasonably immunogenic, and suitable for further evaluation.
Adult↗
Virulence of a live dengue virus vaccine candidate: a possible new marker of dengue virus attenuation.
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Adult↗
Lack of attenuation of a candidate dengue 1 vaccine (45AZ5) in human volunteers.
A dengue type 1, candidate live virus vaccine (45AZ5) was prepared by serial virus passage in fetal rhesus lung cells. Infected cells were treated with a mutagen, 5-azacytidine, to increase the likelihood of producing attenuated variants. The vaccine strain was selected by cloning virus that produced only small plaques in vitro and showed reduced replication at high temperatures (temperature sensitivity). Although other candidate live dengue virus vaccines selected for similar growth characteristics have been attenuated for humans, two recipients of the 45AZ5 virus developed unmodified acute dengue fever. Viremia was observed within 24 hr of inoculation and lasted 12 to 19 days. Virus isolates from the blood produced large plaques in cell culture and showed diminished temperature sensitivity. The 45AZ5 virus is unacceptable as a vaccine candidate. This experience points out the uncertain relationship between in vitro viral growth characteristics and virulence factors for humans.
Adult↗
Induced oral infection of the owl monkey (Aotus trivirgatus) with hepatitis A virus.
Several species of nonhuman primates have served as animal models for hepatitis A virus (HAV) infection and disease. This study was to determine the suitability of Aotus trivirgatus as an orally induced model for HAV infection and to reconfirm the owl monkey's susceptibility to the intravenous route of inoculation. Animals were inoculated, either orally or intravenously, with varying concentrations of PA-33 strain of HAV. Serum enzymes ALT, AST and GGTP levels were monitored and liver biopsies performed when values exceeded three standard deviations above individualized mean baseline values. All animals had postinoculation elevations of serum ALT and AST values, shed virus in their feces, and were seropositive to HAV by 60 days after inoculation. Eight of the ten postinoculation biopsy specimens had histologic lesions compatible with acute viral hepatitis. We conclude that the owl monkey is a useful and valuable model for the study of HAV disease.
Administration, Oral↗
Current status of dengue vaccines and prospects for the future.
Dengue vaccine development is complicated by the existence of four viral serotypes, the lack of in vitro assays of virulence for humans and the lack of an animal model for assessing viral attenuation. Experience gained from human testing shows that the in vitro phenotypic growth characteristics used for selecting candidate dengue viruses do not always correlate with lack of pathogenicity in vivo. While testing continues on live, attenuated, viral strains, alternative dengue vaccine products produced as recombinant subunit vaccines are being sought.
Antibodies, Viral↗
Clinical significance of low molecular weight (7-8S) immunoglobulin M antibody to hepatitis B core antigen in chronic hepatitis B virus infections.
Separation of 7-8S and 19S forms of serum immunoglobulin M (IgM) hepatitis B core antibody (anti-HBc) by rate-zonal centrifugation was carried out on serum from 80 American chronic carriers of hepatitis B surface antigen (HBsAg), all of whom were positive for IgM anti-HBc and had elevated levels of serum alanine aminotransferase (mean 164 IU/L). Seventy-three of the 80 sera showed a predominance of one or the other form of IgM anti-HBc. Fifty-four (68%) had predominantly 7-8S IgM anti-HBc, and 19 (24%) had predominantly 19S IgM anti-HBc. Sex, age, length of HBsAg-carrier state, mean alanine aminotransferase, mean total IgM anti-HBc level, presence of hepatitis B e antigen, and liver histology were similar in both groups. 19S IgM anti-HBc was detected in 11 (41%) of 27 male homosexuals compared with only 8 (17%) of 46 heterosexual patients (p = 0.03). Despite this apparent association, an explanation for the variable presence of 19S and 7-8S IgM anti-HBc predominance in chronic hepatitis B remains lacking.
Adolescent↗
Preparation of a prototype inactivated hepatitis A virus vaccine from infected cell cultures.
Studies were conducted on the preparation, inactivation, safety, and immunogenicity of a prototype hepatitis A virus vaccine prepared from infected cell cultures. BS-C-1 cells maintained in medium 199 without serum were infected with the HM175 strain of hepatitis A virus and harvested after 21-28 days. The harvested virus preparation contained 6.8-7.4 (log 10) cell culture infectious doses/ml. After exposure to 1:4,000 formalin at 35 C, the infectivity titer decreased 10(6)-fold in 30 hr at an exponential rate, although virus was detected in 5.0-ml vaccine samples for up to three days. Three separate vaccine lots elicited antibody in all the guinea pigs given three doses. Owl monkeys given three doses of vaccine did not have any evidence of HAV infection but developed antibodies identifiable by radioimmunoassay and serum neutralization tests. After either oral or intravenous challenge with at least 10(6) monkey infectious doses of a virulent field strain of hepatitis A virus, none of the vaccinated monkeys shed virus in their feces or had elevated serum levels of alanine aminotransferase. The findings suggest that an effective inactivated whole virus hepatitis A vaccine can be prepared from cell culture.
Animals↗
Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine. A cost reduction strategy.
High cost and limited availability of the current hepatitis B virus vaccine lead to underutilization. To address this problem, we performed a vaccine trial comparing the currently recommended regimen of 20 micrograms of hepatitis B surface antigen (HBsAg) intramuscularly on days 0, 30, and 180, with a more economical regimen of 2 micrograms of HBsAg intradermally on days 0, 30, and 180. This trial was performed in 50 seronegative health care workers to assess the immunogenicity and local reactogenicity of both vaccine regimens. We found no significant difference in seroconversion between the intradermal group (96%) and the intramuscular group (100%). Mean ratios of test sample value to mean negative control value for antibody to HBsAg at 360 days were not significantly different (intradermal group, 84 +/- 26; intramuscular group, 120 +/- 22). Reactions in both groups were minor. Although the optimal dose of HBsAg was not investigated, our data demonstrate that 0.1 mL of inactivated hepatitis B virus vaccine (Heptavax-B) intradermally is immunogenic in healthy adults. Vaccination by this regimen can broaden hepatitis B virus disease prevention.
Adult↗
Human lymphocyte responses to hepatitis A virus-infected cells: interferon production and lysis of infected cells.
Peripheral blood mononuclear cells (PBMC) from nonimmune healthy donors who did not have antibody to hepatitis A virus lysed hepatitis A virus-infected BS-C-1 cells to a greater degree than uninfected BS-C-1 cells. The predominant effector cells were contained in the nonadherent peripheral blood lymphocyte (PBL) fraction, although some lytic activity was associated with adherent cells. Characterization of the PBL with monoclonal antibodies showed that the responsible effector lymphocytes were contained in Leu-11+ and M1+ subsets, but not in the T3+ or T4+ subsets. The phenotypes of the effector cells active in the lysis of hepatitis A virus-infected cells are similar to those of human natural killer cells that lyse K562 cells. Human PBL produced high titers of interferon-alpha (IFN-alpha) when exposed to hepatitis A virus-infected cells. These results imply that hepatitis A virus infection may be controlled by lymphocyte responses in the liver, i.e., by lymphocyte-mediated lysis of the hepatitis A virus-infected cells, and by the production of high titers of IFN-alpha by lymphocytes exposed to hepatitis A virus-infected cells. Furthermore, these results, along with the observations that hepatitis A virus infection results in a persistent noncytocidal infection in vitro, support the hypothesis that lysis of hepatocytes infected with hepatitis A virus is by lymphocyte-mediated cytotoxicity and not by virus-induced destruction of the liver cell.
Antibodies, Monoclonal↗
The association of enhancing antibodies with seroconversion in humans receiving a dengue-2 live-virus vaccine.
A group of human subjects, some with yellow fever (YF) antibodies, volunteered for testing of a live-attenuated dengue-2 (DEN-2) vaccine. Serum samples taken before DEN-2 vaccination were tested for their ability to enhance infection of human monocytes by DEN-2 virus. A significantly greater proportion of enhancing antibodies (Eab) were found in YF-immune (YFI) individuals (50%) as compared to those with no evidence of flavivirus infection (9.5%). Geometric mean titers of neutralizing and hemagglutination inhibiting antibodies to DEN-2 virus in YFI subjects with Eab were fourfold to seven-fold higher than in the YFI subjects without Eab in prevaccine sera and 10- to 35-fold higher than in non-immune volunteers. Additionally, levels of Eab in prevaccine sera were directly related to antibody titers found in postvaccine sera. The presence of Eab in the serum of a human subject before DEN-2 vaccination was a good predictor of the immune response after vaccination, and may in part be responsible for the higher seroconversion rate in YF immunes (90%) as compared to nonimmunes (61%) receiving this vaccine. This is the first human study to demonstrate that circulating Eab in non-DEN-immune persons is associated with an augmented immune response to DEN virus infection. This finding supports the hypothesis that cross-reactive antibodies against one flavivirus enhance an infection with another closely related flavivirus.
Adjuvants, Immunologic↗
Human hypersensitivity to a sham vaccine prepared from mosquito-cell culture fluids.
A sham vaccine, prepared with the C6/36 cell line derived from larval Aedes albopictus mosquitoes, was skin tested on 12 volunteers. Although no reactions were observed after prick tests, three immediate reactions did occur after intradermal tests. Subcutaneous administration of the C6/36 sham vaccine was initially performed on the nine subjects who did not demonstrate immediate reactions. Five of these subjects developed delayed reactions at the site of the intradermal test within 12 hr after inoculation. A Prausnitz-Küstner test was performed on the back of one unsensitized subject by use of both unheated and heated sera from three subjects who had immediate skin reactions, three who demonstrated a delayed reaction, and one who had a negative skin response. In the Prausnitz-Küstner test, immediate skin reactions were observed with all seven unheated sera but with none of the heated serum aliquots. The determination that skin reactivity was associated with a heat-labile serum factor suggested the mechanism was IgE-mediated. Under close surveillance, the C6/36 sham vaccine was administered subcutaneously to one volunteer who had previously demonstrated an immediate response. This subject developed an anaphylactic reaction characterized by hives at the site and more distantly from the site of the subcutaneous inoculation. Hypersensitivity to A. albopictus larval antigens is common and precludes the use of C6/36 cell culture as a substrate for viral vaccines.
Cells, Cultured↗
Dengue virus type 2 vaccine: reactogenicity and immunogenicity in soldiers.
A live dengue virus type 2 (dengue-2) vaccine (PR-159/S-1) was tested for reactogenicity and immunogenicity in a placebo-controlled, double-blind clinical trial involving 98 soldiers. Seroconversion rates based on the development of neutralizing antibody to dengue-2 were 90% in 70 recipients with immunity to yellow fever and 61% in 28 vaccinees without such immunity (P less than .01). Peak titers of neutralizing antibody were three times higher in recipients with antibody to yellow fever virus and persisted in most for at least 18 months. Individuals seroconverting to the vaccine virus more frequently experienced systemic symptoms than those who received placebo (P less than .02). Future users of this dengue-2 vaccine may wish to employ immunization schedules that include preliminary immunization against yellow fever and must be prepared to accept mild vaccine-related symptoms in some recipients.
Adolescent↗
Primary isolation and serial passage of hepatitis A virus strains in primate cell cultures.
Although several primate cell types have been reported to support replication of hepatitis A virus, optimal conditions for the isolation and production of quantities of virus have not been defined. We therefore examined seven different primate cell types for their ability to support replication of primate-passaged and wild-type virus as reflected by intracytoplasmic accumulation of viral antigen (direct immunofluorescence and radioimmunoassay) and propagation of cell culture-adapted virus. Of the cells tested, low-passage African green monkey kidney (AGMK) cells were most sensitive for initial isolation. Viral replication was documented after inoculation of AGMK cells with seven of nine hepatitis A virus antigen-positive fecal specimens (from seven epidemiologically distinct sources). With six inocula, virus was successfully passed in serial cultures. AGMK-adapted virus was readily propagated in continuous AGMK (BS-C-1) cells. The optimal temperature for the growth of virus in BS-C-1 cells was 35 degrees C. Viral release into supernatant fluids was documented in the absence of any cytopathic effect, and infectivity titers in supernatant fluids 21 days after inoculation (50% tissue culture infective does [TCID50], 10(6.0)/ml) equalled or exceeded those in the cell fraction (TCID50, 10(5.5)/ml). Cells maintained in serum-free media readily supported viral growth, with yields of virus (TCID50, 10(6.5)/ml) equal to or greater than those obtained with cells maintained in 2% fetal bovine serum.
Animals↗
Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. V. Human response to immunization with a candidate vaccine prepared in fetal rhesus lung cells.
A dengue 4 (strain H241, PDK35-TD3 FRhL p3) vaccine attenuated by passage in primary dog kidney cells followed by passage and final vaccine preparation in DBS-FRhL-2 cells was tested in five yellow fever-immune volunteers. Only two volunteers seroconverted by producing hemagglutination-inhibiting and neutralizing antibodies. Mild illness, compatible with dengue infection was found only in the individuals who later developed antibodies. Both volunteers developed a rash by the 8th day following vaccination, coinciding with a slight elevation in temperature and leukopenia. Additionally, several serum enzymes were elevated during the observation period. Dengue 4 virus was isolated from the blood of the two infected volunteers starting as early as day 5 post vaccination. During the viremic period, which lasted 5 days, phenotypically-changed virus was recovered, indicating genetic instability of the vaccine virus. The clinical disease and immune response in the two infected individuals was probably related to replication of the variant virus. Further testing of this vaccine in its present form is not indicated.
Adult↗