Ira M. Longini

The Transmissibility and Control of Pandemic Influenza A (H1N1) Virus

Flus Tricky Tricks After vaccination against influenza A virus, single-point mutations are selected in hemagglutinin (the virus molecule that binds to sialic acid molecules on the surface of host cells) that escape neutralization by polyclonal antibody responses. Hensley et al. (p. 734) have discovered that in mice these mutations increased the viruss avidity for sialic acid. Amino acid substitutions that occur during reiterations of immune escape and avidity modulation can thus drive antigenic variation. This constant evolution of influenza viruses requires us to change vaccine components annually, and, for equine influenza, Park et al. (p. 726) show that as the match between virus and vaccine strains drifts apart with time, the probability of becoming infected and the length of the infectious period increase to the point where outbreaks occur. Nevertheless, even imperfect vaccines may be of benefit to a population because increasing the proportion of vaccinated individuals can supply enough herd immunity to offset a poor antigenic match, especially if used in conjunction with antiviral drugs. For humans, Yang et al. (p. 729, published online 10 September) estimate that the rate of transmission within U.S. households puts influenza A 2009 H1N1 (the current pandemic “swine flu”) in the higher range of transmissibility, compared to past seasonal and pandemic strains. Thus, to achieve mitigation this fall, children should be the first recipients of vaccine, followed by adults—aiming overall for 70% coverage of the population. A detailed picture of the pandemic potential of swine-origin influenza offers guidance for effective mitigation strategies. Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has become the dominant strain in the Southern Hemisphere, where the influenza season has now ended. Here, on the basis of reported case clusters in the United States, we estimated the household secondary attack rate for pandemic H1N1 to be 27.3% [95% confidence interval (CI) from 12.2% to 50.5%]. From a school outbreak, we estimated that a typical schoolchild infects 2.4 (95% CI from 1.8 to 3.2) other children within the school. We estimated the basic reproductive number, R0, to range from 1.3 to 1.7 and the generation interval to range from 2.6 to 3.2 days. We used a simulation model to evaluate the effectiveness of vaccination strategies in the United States for fall 2009. If a vaccine were available soon enough, vaccination of children, followed by adults, reaching 70% overall coverage, in addition to high-risk and essential workforce groups, could mitigate a severe epidemic.

Modeling targeted layered containment of an influenza pandemic in the United States

Planning a response to an outbreak of a pandemic strain of influenza is a high public health priority. Three research groups using different individual-based, stochastic simulation models have examined the consequences of intervention strategies chosen in consultation with U.S. public health workers. The first goal is to simulate the effectiveness of a set of potentially feasible intervention strategies. Combinations called targeted layered containment (TLC) of influenza antiviral treatment and prophylaxis and nonpharmaceutical interventions of quarantine, isolation, school closure, community social distancing, and workplace social distancing are considered. The second goal is to examine the robustness of the results to model assumptions. The comparisons focus on a pandemic outbreak in a population similar to that of Chicago, with ≈8.6 million people. The simulations suggest that at the expected transmissibility of a pandemic strain, timely implementation of a combination of targeted household antiviral prophylaxis, and social distancing measures could substantially lower the illness attack rate before a highly efficacious vaccine could become available. Timely initiation of measures and school closure play important roles. Because of the current lack of data on which to base such models, further field research is recommended to learn more about the sources of transmission and the effectiveness of social distancing measures in reducing influenza transmission.

Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial

BACKGROUND A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. METHODS For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. INTERPRETATION The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. FUNDING WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development.

Role of the primary infection in epidemics of HIV infection in gay cohorts.

A review of the data on infectivity per contact for transmission of the HIV suggests that the infectivity may be on the order of 0.1-0.3 per anal intercourse in the period of the initial infection, 10(-4) to 10(-3) in the long asymptomatic period, and 10(-3) to 10(-2) in the period leading into AIDS. The pattern of high contagiousness during the primary infection followed by a large drop in infectiousness may explain the pattern of epidemic spread seen in male homosexual cohorts in the early years of the epidemic. Simulations of cohorts of homosexual males, using that range of parameter values, indicate the following: (a) The initial fast rise and then more or less rapid flattening of the incidence curve of seropositives is primarily due to rapid initial spread, yielding a group of infecteds all of whom pass into the low infectivity asymptomatic period at close to the same time. All this occurs only if the basic reproduction number for the primary infection is > 1. (b) The behavioral changes that have been reported all started after the incidence of new infections began to fall, too late to have a major effect on the initial rise. The behavioral changes had a major effect in slowing down the subsequent rise in the number of seropositives. (c) High activity groups play an important role in the early rapid rise of the epidemic. However, it is not likely that the rapid decrease in rate of growth of seropositives is solely due to saturation of these very high activity groups. Although the evidence for this interpretation of the role of the primary infection is not conclusive, its implications for prevention and for vaccine trials are so markedly different from those of other interpretations that we consider it to be an important hypothesis for further testing.

DURATION OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION BEFORE DETECTION OF ANTIBODY

To estimate the duration and frequency of the period of HIV infection without detectable antibody, modelling techniques were applied to results of detection of HIV DNA by means of the polymerase chain reaction (PCR) and to data from cases in published reports. PCR was carried out with gag and env region primers on samples from 27 homosexual and 12 haemophilic men for whom stored samples were available from before and after seroconversion; serum was also tested for p24 antigen by antigen-capture enzyme immunoassay. HIV DNA was detectable before seroconversion in 4 men; in all 4 PCR was positive only in the seronegative sample taken closest to the time of seroconversion. In 3 men antigen was detected before seroconversion; in each case HIV DNA was also detected. By a Markov model, the time from infection with HIV (as assessed by detection of HIV DNA) to first detection of HIV antibody was estimated to be 2.4 (SE 2.1) months for the median individual. Modelling of cases of HIV infection with known exposure in published reports gave a median estimate of 2.1 (0.1) months from exposure to antibody detection, and 95% of cases would be expected to seroconvert within 5.8 (0.6) months. HIV infection for longer than 6 months without detectable antibody seems uncommon.

Critical Factors Influencing the Occurrence of Vibrio cholerae in the Environment of Bangladesh

ABSTRACT The occurrence of outbreaks of cholera in Africa in 1970 and in Latin America in 1991, mainly in coastal communities, and the appearance of the new serotype Vibrio cholerae O139 in India and subsequently in Bangladesh have stimulated efforts to understand environmental factors influencing the growth and geographic distribution of epidemic Vibrio cholerae serotypes. Because of the severity of recent epidemics, cholera is now being considered by some infectious disease investigators as a “reemerging” disease, prompting new work on the ecology of vibrios. Epidemiological and ecological surveillance for cholera has been under way in four rural, geographically separated locations in Bangladesh for the past 4 years, during which both clinical and environmental samples were collected at biweekly intervals. The clinical epidemiology portion of the research has been published (Sack et al., J. Infect. Dis. 187:96-101, 2003). The results of environmental sampling and analysis of the environmental and clinical data have revealed significant correlations of water temperature, water depth, rainfall, conductivity, and copepod counts with the occurrence of cholera toxin-producing bacteria (presumably V. cholerae). The lag periods between increases or decreases in units of factors, such as temperature and salinity, and occurrence of cholera correlate with biological parameters, e.g., plankton population blooms. The new information on the ecology of V. cholerae is proving useful in developing environmental models for the prediction of cholera epidemics.

Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics

The Bill and Melinda Gates Foundation supports an ambitious portfolio of novel vaccines, drug regimens, and diagnostic tools for tuberculosis (TB). We elicited the expected efficacies and improvements of the novel interventions in discussions with the foundations managing their development. Using an age-structured mathematical model of TB, we explored the potential benefits of novel interventions under development and those not yet in the portfolio, focusing on the WHO Southeast Asia region. Neonatal vaccination with the portfolio vaccine decreases TB incidence by 39% to 52% by 2050. Drug regimens that shorten treatment duration and are efficacious against drug-resistant strains reduce incidence by 10–27%. New diagnostics reduce incidence by 13–42%. A triple combination of a portfolio vaccine, drug regimen, and diagnostics reduces incidence by 71%. A short mass vaccination catch-up campaign, not yet in the portfolio, to augment the triple combination, accelerates the decrease, preventing >30% more cases by 2050 than just the triple combination. New vaccines and drug regimens targeted at the vast reservoir of latently infected people, not in the portfolio, would reduce incidence by 37% and 82%, respectively. The combination of preventive latent therapy and a 2-month drug treatment regimen reduces incidence by 94%. Novel technologies in the pipeline would achieve substantial reductions in TB incidence, but not the Stop TB Partnership target for elimination. Elimination will require new delivery strategies, such as mass vaccination campaigns, and new products targeted at latently infected people.

Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa

Background Extensive evidence from observational studies suggests a role for genital herpes in the HIV epidemic. A number of herpes vaccines are under development and several trials of the efficacy of HSV-2 treatment with acyclovir in reducing HIV acquisition, transmission, and disease progression have just reported their results or will report their results in the next year. The potential impact of these interventions requires a quantitative assessment of the magnitude of the synergy between HIV and HSV-2 at the population level. Methods and Findings A deterministic compartmental model of HIV and HSV-2 dynamics and interactions was constructed. The nature of the epidemiologic synergy was explored qualitatively and quantitatively and compared to other sexually transmitted infections (STIs). The results suggest a more substantial role for HSV-2 in fueling HIV spread in sub-Saharan Africa than other STIs. We estimate that in settings of high HSV-2 prevalence, such as Kisumu, Kenya, more than a quarter of incident HIV infections may have been attributed directly to HSV-2. HSV-2 has also contributed considerably to the onward transmission of HIV by increasing the pool of HIV positive persons in the population and may explain one-third of the differential HIV prevalence among the cities of the Four City study. Conversely, we estimate that HIV had only a small net impact on HSV-2 prevalence. Conclusions HSV-2 role as a biological cofactor in HIV acquisition and transmission may have contributed substantially to HIV particularly by facilitating HIV spread among the low-risk population with stable long-term sexual partnerships. This finding suggests that prevention of HSV-2 infection through a prophylactic vaccine may be an effective intervention both in nascent epidemics with high HIV incidence in the high risk groups, and in established epidemics where a large portion of HIV transmission occurs in stable partnerships.

Probability of female-to-male transmission of HIV-1 in Thailand

The epidemic of human immunodeficiency virus type 1 (HIV-1) infection in Thailand has allowed an estimate to be made of the probability of female-to-male HIV-1 transmission per sexual contact. In a study of 1115 21-year-old male military conscripts, of whom 77 (6.9%) were HIV-1 seropositive, sex with female prostitutes was identified as the principal mode of HIV-1 transmission. With a mathematical model including data on conscripts age at first sexual contact, frequency of sex with female prostitutes, and province of origin; as well as province-specific HIV-1 seroprevalence of prostitutes, we estimated the probability of HIV-1 transmission per sexual contact to be 0.031 (95% confidence limits [CL] 0.025-0.040). Allowing for random error in the self-reported frequency of contacts, the estimate was 0.056 (95% CL 0.041-0.075). The transmission probability was significantly greater among men with a history of sexually-transmitted diseases. These estimates are substantially higher than analogous estimates made in North America. This high per-act probability of heterosexual transmission helps to explain the rapid spread of HIV-1 in the emerging epidemic in Thailand and perhaps in other countries where HIV-1 transmission is predominantly heterosexual.

Assessing the International Spreading Risk Associated with the 2014 West African Ebola Outbreak

Background: The 2014 West African Ebola Outbreak is so far the largest and deadliest recorded in history. The affected countries, Sierra Leone, Guinea, Liberia, and Nigeria, have been struggling to contain and to mitigate the outbreak. The ongoing rise in confirmed and suspected cases, 2615 as of 20 August 2014, is considered to increase the risk of international dissemination, especially because the epidemic is now affecting cities with major commercial airports. Method: We use the Global Epidemic and Mobility Model to generate stochastic, individual based simulations of epidemic spread worldwide, yielding, among other measures, the incidence and seeding events at a daily resolution for 3,362 subpopulations in 220 countries. The mobility model integrates daily airline passenger traffic worldwide and the disease model includes the community, hospital, and burial transmission dynamic. We use a multimodel inference approach calibrated on data from 6 July to the date of 9 August 2014. The estimates obtained were used to generate a 3-month ensemble forecast that provides quantitative estimates of the local transmission of Ebola virus disease in West Africa and the probability of international spread if the containment measures are not successful at curtailing the outbreak. Results: We model the short-term growth rate of the disease in the affected West African countries and estimate the basic reproductive number to be in the range 1.5 − 2.0 (interval at the 1/10 relative likelihood). We simulated the international spreading of the outbreak and provide the estimate for the probability of Ebola virus disease case importation in countries across the world. Results indicate that the short-term (3 and 6 weeks) probability of international spread outside the African region is small, but not negligible. The extension of the outbreak is more likely occurring in African countries, increasing the risk of international dissemination on a longer time scale.