Epidemiological Consequences of Imperfect Vaccines for Immunizing Infections

The control of some childhood diseases has proven to be difficult even in countries that maintain high vaccination coverage. This may be due to the use of imperfect vaccines and there has been much discussion on the different modes by which vaccines might fail. To understand the epidemiological implications of some of these different modes, we performed a systematic analysis of a model based on the standard SIR equations with a vaccinated component that permits vaccine failure in degree (“leakiness”), take (“all-or-nothingness”) and duration (waning of vaccine-derived immunity). The model was first considered as a system of ordinary differential equations, then extended to a system of partial differential equations to accommodate age structure. We derived analytic expressions for the steady states of the system and the final age distributions in the case of homogenous contact rates. The stability of these equilibria are determined by a threshold parameter R(p), a function of the vaccine failure parameters and the coverage p. The value of p for which R(p) = 1 yields the critical vaccination ratio, a measure of herd immunity. Using this concept we can compare vaccines that confer the same level of herd immunity to the population but may fail at the individual level in different ways. For any fixed R(p) > 1, the leaky model results in the highest prevalence of infection, while the all-or-nothing and waning models have the same steady state prevalence. The actual composition of a vaccine cannot be determined on the basis of steady state levels alone, however the distinctions can be made by looking at transient dynamics (such as after the onset of vaccination), the mean age of infection, the age distributions at steady state of the infected class, and the effect of age-specific contact rates

Impact populationnel de l'adoption d'un calendrier mixte de vaccination contre les virus du papillome humain au Québec : une étude de modélisation

En 2018, la province de Québec a modifié son calendrier de vaccination contre les virus du papillome humain (VPH), remplaçant le calendrier comportant 2 doses de vaccin nonavalent par un calendrier de vaccination mixte, comportant une dose de vaccin nonavalent suivie d’une dose de vaccin bivalent. Toutefois, l’efficacité clinique et la durée de protection conférées par ce calendrier mixte ne sont pas connues avec précision, impliquant une incertitude quant à son impact populationnel sur l’incidence des maladies associées aux VPH. L’impact populationnel du calendrier mixte au Québec a été évalué à l’aide d’une étude de modélisation mathématique. Le modèle utilisé (HPV-ADVISE) est basé sur les individus et simule la dynamique de transmission des VPH à l’échelle populationnelle. Les mesures d’impact considérées incluent la réduction prédite par le modèle du taux d’incidence et du nombre total de cas des maladies attribuables aux VPH. L’effet de l’incertitude quant à l’efficacité vaccinale et la durée de protection sur l’impact du calendrier mixte a été exploré à l’aide d’analyses de sensibilité univariées. Pour les lésions cancéreuses et précancéreuses, les simulations ont globalement prédit une faible différence d’impact entre les scénarios les plus plausibles du calendrier mixte et le calendrier comportant 2 doses de vaccin nonavalent, conséquence de l’importance inférieure du fardeau attribuable aux génotypes 31/33/45/52/58 comparativement aux génotypes 16/18. L’impact sur l’incidence des condylomes s’est avéré beaucoup plus sensible à la durée de protection qu’à l’efficacité vaccinale. Pour les scénarios jugés plausibles, la réduction à long terme du taux d’incidence des condylomes a été prédite entre ~ 50 % (durée de protection de 20 ans) et 90 % (protection à vie, efficacité de 75 à 100 %). Cette grande variabilité dans les prédictions du modèle suggère qu’une surveillance populationnelle des infections à VPH et des condylomes suite à l’implantation du calendrier mixte pourrait être indiquée.In 2018, the province of Québec (Canada) modified its vaccination schedule against human papilloma virus (HPV), replacing the 2-dose nonavalent schedule by a mixed schedule, comprising a single dose of nonavalent vaccine followed by a single dose of bivalent vaccine. However, clinical efficacy and duration of protection conferred by this mixed schedule are not known precisely, implying a level of uncertainty with respect to its population-level impact on HPV-associated diseases. The population-level impact of mixed HPV vaccination in Québec was examined with a mathematical modeling study. We used an individual-based model (HPV-ADVISE) that simulates HPV transmission dynamics at the population level. Impact measures that were considered in this study include model-predicted percentage reduction in incidence rate and in total number of cases of diseases attributable to HPV infections. The effect of uncertainty regarding vaccine efficacy and duration of protection on mixed schedule populational impact was explored with deterministic univariate sensitivity analyses. For precancerous and cancerous lesions attributable to HPV infections, the model globally predicted a small impact difference between the more plausible scenarios for the mixed schedule and the 2-dose nonavalent schedule. This is a consequence of the lesser populational importance of the disease burden attributable to genotypes 31/33/45/52/58 compared to genotypes 16/18. The impact on condyloma (anogenital warts) incidence proved much more sensitive to duration of protection compared to vaccine efficacy. For plausible mixed schedule scenarios, long-term percentage reduction of condyloma incidence rate was predicted between ~ 50 % (20 years protection scenario) and 90 % (lifelong protection and 75 % to 100 % efficacy scenarios). The high variability in model predictions within plausible scenarios suggests that populational surveillance of HPV infections and condyloma incidence following the introduction of the mixed schedule could be indicated

Estudio del efecto de la vacunación en modelos de epidemias con transmisión estocástica

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Estudios Estadísticos, leída el 15-12-2022Mathematical epidemic models are frequently used in biology for analyzing transmission dynamics of infectious diseases and assessing control measures to interrupt their expansion. In order to select and develop properly the above mathematical models, it is necessary to take into account the particularities of an epidemic process as type of disease, mode of transmission and population characteristics. In this thesis we focus on infectious diseases with stochastic transmission including vaccination as a control measure to stop the spread of the pathogen. To that end, we consider constant and moderate size populations where individuals are homogeneously mixed. We assume that characteristics related to the transmission/recovery of the infectious disease present a common probabilistic behavior for individuals in the population. To assure herd immunity protection, we consider that a percentage of the population is protected against the disease by a vaccine, prior to the start of the outbreak.The administered vaccine is imperfect in the sense that some individuals, who have been previously vaccinated, failed to increase antibody levels and, in consequence, they could be infected. Pathogenic transmission occurs by direct contact with infected individuals. As population is not isolated, disease spreads from direct contacts with infected individuals inside or outside the population...Los modelos matemáticos epidemiológicos se usan frecuentemente en biología para analizar las dinámicas de transmisión de enfermedades infecciosas y para evaluar medidas de control con el objetivo de frenar su expansión. Para poder seleccionar y desarrollar adecuadamente estos modelos es necesario tener en cuenta las particularidades propias del proceso epidémico tales como el tipo de enfermedad, modo de transmisión y características de la población. En esta tesis nos centramos en el estudio de enfermedades de tipo infeccioso con transmisión por contacto directo, que disponen de una vacuna como medida de contención en la propagación del patógeno. Para ello, consideramos poblaciones de tamaño moderado, que permanece constante a lo largo de un brote y asumiremos que los individuos no tienen preferencia a la hora de relacionarse y que las características referentes a la transmisión de la enfermedad se representan en términos de variables aleatorias, comunes para todos los individuos. La población no está aislada y la transmisión del patógeno se produce mediante contacto directo con cualquier persona infectada, tanto de dentro de la población como fuera de ella. Asumimos que, antes del inicio del brote epidémico, se ha administrado la vacuna a un porcentaje suficiente de individuos de la población, de forma que se asegure la inmunidad de rebaño. Consideramos que la vacuna administrada es imperfecta en el sentido que algunos individuos vacunados no logran desarrollar anticuerpos frente a la enfermedad y por lo tanto, podrían resultar infectados al contactar con individuos enfermos...Fac. de Estudios EstadísticosTRUEunpu

The Drivers of Acute Seasonal Infectious Diseases.

Seasonality is a feature of all ecological systems. Earth's terrestrial and pelagic life has evolved in a highly seasonal abiotic environment with intra-annual variation in photoperiod, temperature, and precipitation, among many other abiotic and biotic factors. Seasonal aspects of mammals and birds include seasonally varying birth rates, seasonal changes in endocrine hormones, and seasonal variation in immunity. One area where seasonal biology is particularly salient is disease ecology. The mechanisms underlying the seasonality of communicable diseases are poorly understood. I propose that much of the unexplained seasonality observed in infectious disease dynamics could be attributed to seasonal biology, including (1) birth seasonality, (2) seasonal variation in immunity, and (3) seasonal cycles in parasite traits and parasite population parameters. In my dissertation, I present work on various aspects of seasonality. In Chapter II, I explored the seasonality of births in human populations and quantified the effects of birth seasonality on measles epidemics. In Chapter III, I reviewed circadian and circannual rhythms in host and parasite populations, and proposed both ecological and evolutionary models for integrating biological rhythms into the study of infectious diseases. In Chapters IV--V, I presented my in-depth ecological studies of poliovirus, a notoriously seasonal summertime infection. I explored geographical variation in polio's seasonality and tested whether human birth seasonality or transmission seasonality drove epidemics of this disease. In addition to studying polio seasonality, I revealed the connection between (i) polio's emergence and human demography, (ii) the geographical distribution of poliovirus and its persistence, and (iii) polio symptomatology and silent chains of transmission. Lastly, I highlighted the public health implications of seasonal transmission by measuring the efficacy of the two polio vaccines and discussing how seasonality can be utilized for vaccine interventions.PhDEcology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/113643/1/bakkerma_1.pd