Michiel van Boven

Avian Influenza A Virus (H7N7) Epidemic in The Netherlands in 2003: Course of the Epidemic and Effectiveness of Control Measures

An epidemic of high-pathogenicity avian influenza (HPAI) A virus subtype H7N7 occurred in The Netherlands in 2003 that affected 255 flocks and led to the culling of 30 million birds. To evaluate the effectiveness of the control measures, we quantified between-flock transmission characteristics of the virus in 2 affected areas, using the reproduction ratio Rh. The control measures markedly reduced the transmission of HPAI virus: Rh before detection of the outbreak in the first infected flock was 6.5 (95% confidence interval [CI], 3.1-9.9) in one area and 3.1 in another area, and it decreased to 1.2 (95% CI, 0.6-1.9) after detection of the first outbreak in both areas. The observation that Rh remained >1 suggests that the containment of the epidemic was probably due to the reduction in the number of susceptible flocks by complete depopulation of the infected areas rather than to the reduction of the transmission by the other control measures.

Risk Maps for the Spread of Highly Pathogenic Avian Influenza in Poultry

Devastating epidemics of highly contagious animal diseases such as avian influenza, classical swine fever, and foot-and-mouth disease underline the need for improved understanding of the factors promoting the spread of these pathogens. Here the authors present a spatial analysis of the between-farm transmission of a highly pathogenic H7N7 avian influenza virus that caused a large epidemic in The Netherlands in 2003. The authors developed a method to estimate key parameters determining the spread of highly transmissible animal diseases between farms based on outbreak data. The method allows for the identification of high-risk areas for propagating spread in an epidemiologically underpinned manner. A central concept is the transmission kernel, which determines the probability of pathogen transmission from infected to uninfected farms as a function of interfarm distance. The authors show how an estimate of the transmission kernel naturally provides estimates of the critical farm density and local reproduction numbers, which allows one to evaluate the effectiveness of control strategies. For avian influenza, the analyses show that there are two poultry-dense areas in The Netherlands where epidemic spread is possible, and in which local control measures are unlikely to be able to halt an unfolding epidemic. In these regions an epidemic can only be brought to an end by the depletion of susceptible farms by infection or massive culling. The analyses provide an estimate of the spatial range over which highly pathogenic avian influenza viruses spread between farms, and emphasize that control measures aimed at controlling such outbreaks need to take into account the local density of farms.

Estimation of Transmission Parameters of H5N1 Avian Influenza Virus in Chickens

Despite considerable research efforts, little is yet known about key epidemiological parameters of H5N1 highly pathogenic influenza viruses in their avian hosts. Here we show how these parameters can be estimated using a limited number of birds in experimental transmission studies. Our quantitative estimates, based on Bayesian methods of inference, reveal that (i) the period of latency of H5N1 influenza virus in unvaccinated chickens is short (mean: 0.24 days; 95% credible interval: 0.099–0.48 days); (ii) the infectious period of H5N1 virus in unvaccinated chickens is approximately 2 days (mean: 2.1 days; 95%CI: 1.8–2.3 days); (iii) the reproduction number of H5N1 virus in unvaccinated chickens need not be high (mean: 1.6; 95%CI: 0.90–2.5), although the virus is expected to spread rapidly because it has a short generation interval in unvaccinated chickens (mean: 1.3 days; 95%CI: 1.0–1.5 days); and (iv) vaccination with genetically and antigenically distant H5N2 vaccines can effectively halt transmission. Simulations based on the estimated parameters indicate that herd immunity may be obtained if at least 80% of chickens in a flock are vaccinated. We discuss the implications for the control of H5N1 avian influenza virus in areas where it is endemic.

Herd immunity to Newcastle disease virus in poultry by vaccination.

Newcastle disease is an economically important disease of poultry for which vaccination is applied as a preventive measure in many countries. Nevertheless, outbreaks have been reported in vaccinated populations. This suggests that either the vaccination coverage level is too low or that vaccination does not provide perfect immunity, allowing the virus to spread in partially vaccinated populations. Here we study the requirements of an epidemiologically effective vaccination program against Newcastle disease in poultry, based on data from experimental transmission studies. The transmission studies indicate that vaccinated birds with low or undetectable antibody titres may be protected against disease and mortality but that infection and transmission may still occur. In fact, our quantitative analyses show that Newcastle disease virus is highly transmissible in poultry with low antibody titres. As a consequence, herd immunity can only be achieved if a high proportion of birds (>85%) have a high antibody titre (log2 haemagglutination inhibition titre ≥3) after vaccination. We discuss the implications for the control of Newcastle disease in poultry by vaccination.

Heterozygote advantage fails to explain the high degree of polymorphism of the MHC

Major histocompatibility (MHC) molecules are encoded by extremely polymorphic genes and play a crucial role in vertebrate immunity. Natural selection favors MHC heterozygous hosts because individuals heterozygous at the MHC can present a larger diversity of peptides from infectious pathogens than homozygous individuals. Whether or not heterozygote advantage is sufficient to account for a high degree of polymorphism is controversial, however. Using mathematical models we studied the degree of MHC polymorphism arising when heterozygote advantage is the only selection pressure. We argue that existing models are misleading in that the fitness of heterozygotes is not related to the MHC alleles they harbor. To correct for this, we have developed novel models in which the genotypic fitness of a host directly reflects the fitness contributions of its MHC alleles. The mathematical analysis suggests that a high degree of polymorphism can only be accounted for if the different MHC alleles confer unrealistically similar fitnesses. This conclusion was confirmed by stochastic simulations, including mutation, genetic drift, and a finite population size. Heterozygote advantage on its own is insufficient to explain the high population diversity of the MHC.

Transmission of highly pathogenic avian influenza H5N1 virus in Pekin ducks is significantly reduced by a genetically distant H5N2 vaccine

Domestic ducks play an important role in the epidemiology of H5N1 avian influenza. Although it is known that vaccines that have a high homology with the challenge virus are able to prevent infection in ducks, little is yet known about the ability of genetically more distant vaccines in preventing infection, disease, and transmission. Here we study the effect of a widely used H5N2 vaccine (A/Chicken/Mexico/232/94/CPA) on the transmission of H5N1 virus (A/Chicken/China/1204/04) in ducks. The quantitative analyses show that despite the low level of homology between the virus and vaccine strain transmission was significantly reduced two weeks after a single or double vaccination. Mortality and disease rates were reduced markedly already one week after a single vaccination.

Pathogen adaptation under imperfect vaccination: implications for pertussis

Mass vaccination campaigns have drastically reduced the burden of infectious diseases. Unfortunately, in recent years several infectious diseases have re-emerged. Pertussis poses a well-known example. Inspired by pertussis, we study, by means of an epidemic model, the population and evolutionary dynamics of a pathogen population under the pressure of vaccination. A distinction is made between infection in immunologically naive individuals (primary infection) and infection in individuals whose immune system has been primed by vaccination or infection (secondary infection). The results show that (i) vaccination with an imperfect vaccine may not succeed in reducing the infection pressure if the transmissibility of secondary infections is higher than that of primary infections; (ii) pathogen strains that are able to evade the immunity induced by vaccination can only spread if escape mutants incur no or only a modest fitness cost and (iii) the direction of evolution depends crucially on the distribution of the different types of susceptibles in the population. We discuss the implications of these results for the design and use of vaccines that provide temporary immunity.

The evolutionary economics of immunity

How much of its resources should an individual invest in a costly immune system? In this article, we apply an evolutionarily stable strategy analysis to an epidemic model to answer this question. On the one hand, an investment in immune function confers protection to infectious agents by reducing host susceptibility, pathogen virulence, or the length of the infectious period. On the other hand, an immune system is costly since it absorbs resources that otherwise might be invested in increasing the host’s fertility or longevity. In addition, an active immune system may be able to clear pathogens efficiently but at the same time may result in immunopathology. By means of a reproductive value approach, we show how to compare the costs and benefits of an immune system systematically and how to derive the evolutionarily stable level of immune function. We then apply these methods to various plausible scenarios. The analysis reveals that the relationship between the life span of an organism and the optimal level of investment in immune function is less straightforward than one might expect. First, the prevalence of infection is reduced to the lowest possible level only under special circumstances. Second, members of a long‐lived species do not necessarily have to invest more in immune function than those of a short‐lived species. In fact, the opposite may be true. Third, the outcome of evolution can be contingent on the initial conditions. Depending on its initial investment strategy, a population may evolve to a state where very much or almost nothing is invested in a costly immune system.

Age-Dependent Patterns of Infection and Severity Explaining the Low Impact of 2009 Influenza A (H1N1): Evidence From Serial Serologic Surveys in the Netherlands

Despite considerable research efforts in specific subpopulations, reliable estimates of the infection attack rates and severity of 2009 influenza A (H1N1) in the general population remain scarce. Such estimates are essential to the tailoring of future control strategies. Therefore, 2 serial population-based serologic surveys were conducted, before and after the 2009 influenza A (H1N1) epidemic, in the Netherlands. Random age-stratified samples were obtained using a 2-stage cluster design. Participants donated blood and completed a questionnaire. Data on sentinel general practitioner-attended influenza-like illness and nationwide hospitalization and mortality were used to assess the severity of infection. The estimated infection attack rates were low in the general population (7.6%, 95% confidence interval: 3.6, 11) but high in children aged 5-19 years (35%, 95% confidence interval: 25, 45). The estimated hospitalization and mortality rates per infection increased significantly with age (5-19 years: 0.042% and 0.00094%, respectively; 20-39 years: 0.12% and 0.0025%; 40-59 years: 0.68% and 0.032%; 60-75 years: >0.81% and >0.068%). The high infection attack rate in children and the very low attack rate in older adults, together with the low severity of illness per infection in children but substantial severity in older adults, produced an epidemic with a low overall impact.

Detecting emerging transmissibility of avian influenza virus in human households

Accumulating infections of highly pathogenic H5N1 avian influenza in humans underlines the need to track the ability of these viruses to spread among humans. A human-transmissible avian influenza virus is expected to cause clusters of infections in humans living in close contact. Therefore, epidemiological analysis of infection clusters in human households is of key importance. Infection clusters may arise from transmission events from (i) the animal reservoir, (ii) humans who were infected by animals (primary human-to-human transmission), or (iii) humans who were infected by humans (secondary human-to-human transmission). Here we propose a method of analysing household infection data to detect changes in the transmissibility of avian influenza viruses in humans at an early stage. The method is applied to an outbreak of H7N7 avian influenza virus in The Netherlands that was the cause of more than 30 human-to-human transmission events. The analyses indicate that secondary human-to-human transmission is plausible for the Dutch household infection data. Based on the estimates of the within-household transmission parameters, we evaluate the effectiveness of antiviral prophylaxis, and conclude that it is unlikely that all household infections can be prevented with current antiviral drugs. We discuss the applicability of our method for the detection of emerging human-to-human transmission of avian influenza viruses in particular, and for the analysis of within-household infection data in general.