John F. Brundage

Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness

Summary It is commonly believed that the clinical and epidemiological characteristics of the next influenza pandemic will mimic those of the 1918 pandemic. Determinative beliefs regarding the 1918 pandemic include that infections were expressed as primary viral pneumonias and/or acute respiratory distress syndrome, that pandemic-related deaths were the end states of the natural progression of disease caused by the pandemic strain, and that bacterial superinfections caused relatively fewer deaths in 1918 than in subsequent pandemics. In turn, response plans are focused on developing and/or increasing inventories of a strain-specific vaccine, antivirals, intensive care beds, mechanical ventilators, and so on. Yet, there is strong and consistent evidence of epidemiologically and clinically important interactions between influenza and secondary bacterial respiratory pathogens, including during the 1918 pandemic. Countermeasures (eg, vaccination against pneumococcal and meningococcal disease before a pandemic; mass uses of antibiotic(s) with broad spectrums of activity against common bacterial respiratory pathogens during local epidemics) designed to prevent or mitigate the effects of influenza-bacterial interactions should be major focuses of pandemic-related research, prevention, and response planning.

Deaths from bacterial pneumonia during 1918-19 influenza pandemic.

A sequential-infection hypothesis is consistent with characteristics of this pandemic.

The Defense Medical Surveillance System and the Department of Defense Serum Repository: Glimpses of the Future of Public Health Surveillance

The Defense Medical Surveillance System (DMSS) is the central repository of medical surveillance data for the US armed forces. The DMSS integrates data from sources worldwide in a continuously expanding relational database that documents the military and medical experiences of service members throughout their careers. The Department of Defense Serum Repository (DoDSR) is a central archive of sera drawn from service members for medical surveillance purposes. Currently, the DMSS contains data relevant to more than 7 million individuals who have served in the armed forces since 1990, and the DoDSR contains more than 27 million specimens that are linkable to data in the DMSS. Recent applications of the DMSS and DoDSR provide glimpses of the capabilities and uses of comprehensive public health surveillance systems.

A Phase I Evaluation of the Safety and Immunogenicity of Vaccination with Recombinant gp160 in Patients with Early Human Immunodeficiency Virus Infection

BACKGROUND Despite multiple antiviral humoral and cellular immune responses, infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by post-infection vaccination with HIV-specific antigens. METHODS We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0, 30, and 120 or on days 0, 30, 60, 120, 150, and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination, including general measures of immune function, were monitored. RESULTS In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with greater than 600 cells per milliliter responded, as compared with 6 of 14 [43 percent] with less than or equal to 600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded, as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions, including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up, the mean CD4 count had not decreased in the 19 subjects who responded, but it had decreased by 7.3 percent in the 11 who did not respond. CONCLUSIONS This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful, further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections.

Measurement of the False Positive Rate in a Screening Program for Human Immunodeficiency Virus Infections

In a program screening civilian applicants for U.S. military service for human immunodeficiency virus (HIV) infection, we studied the frequency of false positive diagnoses retrospectively among applicants seropositive for HIV in a subpopulation with a very low prevalence of infection. That subpopulation was defined as consisting of all applicants tested between October 16, 1985, and June 30, 1987, who were young (17 or 18 years of age) and resided in a rural county in a state with a low incidence of reported acquired immunodeficiency syndrome (n = 135,187). Serum specimens from 15 applicants positive for HIV in this low-prevalence subpopulation were retrieved from a serum bank and retested by two Western blot methods, radioimmunoprecipitation, and an immunoassay constructed from a molecularly cloned and expressed viral envelope polypeptide. Fourteen of the 15 samples were unequivocally positive on all retest assays, and 1 was negative. Thus, the measured rate of false positive diagnoses in this program was 1 in 135,187 persons tested. Factors important in achieving a low false positive rate were redundant, multistep testing algorithm, conservative criteria for interpreting Western blots, the requirement that a second, newly drawn serum specimen be tested for verification before a diagnosis of HIV was considered established, and tight quality control of laboratory testing procedures. We conclude that a screening program for HIV infection in a low-prevalence population can have an acceptably low false positive rate.

Human immunodeficiency virus infections among civilian applicants for United States military service, October 1985 to March 1986: Demographic factors associated with seropositivity

During the six months from October 1985 through March 1986, blood samples from 306,061 civilian applicants for military service from the United States were tested for antibody to the human immunodeficiency virus (HIV). Four hundred sixty subjects were positive for the antibody as determined by Western (immune) blot reactivity. The mean prevalence of HIV infection in this population of teenagers and young adults was thus 1.50 per 1000. According to multivariate analysis, the following demographic factors were found to be significant independent predictors of a positive HIV-antibody test: age (adjusted odds ratio = 1.10 per year), black race (adjusted odds ratio = 2.04), male sex (adjusted odds ratio = 1.84), residence in a densely populated county (adjusted odds ratio = 1.05 per 1000 per square mile), and residence in a metropolitan area with a high incidence of the acquired immunodeficiency syndrome (adjusted odds ratio = 1.53). Antibody-positive applicants were identified in 43 of the 50 states. Counties with high prevalence rates for HIV (greater than 5 per 1000) were located in New York State (four counties), New Jersey (three counties), California (two counties), Maryland (two counties), and Texas, Colorado, and Washington, D.C.

Reemergence of Adenovirus Type 4 Acute Respiratory Disease in Military Trainees: Report of an Outbreak during a Lapse in Vaccination

From 23 April to 13 May 1995, an outbreak of acute respiratory disease (ARD) hospitalizations occurred in basic training soldiers at Fort Jackson, South Carolina. Weekly hospitalization rates for the most affected military unit reached 11.6%. Virus isolation and serologic studies from a sample of patients identified the agent as adenovirus type 4. Prior to starting vaccinations against adenovirus types 4 and 7 in 1971, these serotypes were the major causes of ARD in basic trainees. No outbreaks were reported when the vaccines were used. A logistical error temporarily interrupted vaccine production, and newly arriving trainees received no adenovirus vaccines from the summer of 1994 through late March 1995. This outbreak occurred in unvaccinated soldiers. The sole manufacturer has permanently stopped adenovirus vaccine production. All type 4 vaccine supplies are now depleted. This outbreak demonstrates continued susceptibility of military recruits to adenovirus type 4 and warns of future outbreaks.

Pathogenic responses among young adults during the 1918 influenza pandemic.

These responses after secondary exposures caused bacterial pneumonia and most deaths.

Efficacy Testing of Recombinant Human Immunodeficiency Virus (HIV) gp160 as a Therapeutic Vaccine in Early-Stage HIV-1-Infected Volunteers

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Human immunodeficiency virus seropositivity among members of the active duty US Army 1985-89.

Between October 1985 and June 1989, most active duty US Army soldiers were screened for human immunodeficiency virus (HIV) antibody. Of 648,032 screened soldiers in this analysis, 1,588 were HIV-antibody positive. In a multivariate analysis, correlates of positivity included: age [Adjusted Odds Ratios (ref less than 20 years) = 20-24 years, 3.7; 25-29, 9.3; 30-34, 15.7; greater than or equal to 35, 15.9]; being male, [4.2]; being Black or Hispanic (vs white) [3.7 and 3.0, respectively]; being single (vs married) [3.8]; assignment to an HIV endemic location [1.7], and having a medical occupation [2.7, 2.7, and 2.6 for negligible, low, and high blood exposure professions, respectively]. Seropositivity rate ratios for medical vs non-medical personnel were 0.7 [95% CI = 0.4, 1.4] for females and 2.9 [95% CI = 2.5, 3.3] for males. For male medical personnel, being single (vs married) correlated strongly with antibody positivity [prevalence ratio = 3.4, 95% CI = 2.6, 4.6]. Excess HIV risk among medical personnel appeared largely attributable to factors other than occupational exposures.