Biology subjects

Antia, R.

Publications and source records attributed to Antia, R..

3 recordsLinked to original sources

bioRxiv2018

Successes and failures of the live-attenuated influenza vaccine, can we do better?

Live-attenuated vaccines are usually highly effective against many acute viral infections. However, the effectiveness of the live attenuated influenza vaccine (LAIV) can vary widely, ranging from 0% effectiveness in some studies done in the United States to 50% in studies done in Europe. The reasons for these discrepancies remain largely unclear. In this paper we use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The model incorporates two key antigenic distances - the distance between pre-existing immunity and the currently circulating strain as well as the LAIV strain. Our models show that a LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity compared with the circulating strain. The models also suggest two regimes in which LAIV that is matched to circulating strains may provide effective protection. The first is in children before they have built immunity from circulating strains. The second is in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. Our models provide an explanation for the variation in vaccine effectiveness, both between children and adults as well as between studies of vaccine effectiveness observed during the 2014-15 influenza season in different countries.\n\nSignificance StatementThe live-attenuated influenza vaccine, in principle provides an important intervention for the control of both seasonal and pandemic influenza. However vaccine effectiveness studies have found seemingly contradictory results with effectiveness ranging from 0 to 50%. Based on mathematical models we suggest that a major factor responsible for the variable efficacy of the vaccine is negative interference - where pre-existing immunity precludes the vaccine from working. Our models suggest that there are broad regimes for which LAIV will fail to be immunogenic, but also allow us to make suggestions for the choice of vaccine strain that will allow optimization of protective immunity in different scenarios.

epidemiology↗

bioRxiv2018

Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

The high-degree conservation of CD8 T cell epitopes of influenza A virus (IAV) may allow T cell-inducing vaccines effective across different strains and subtypes. This conservation is not fully explained by functional constraint, since additional mutation(s) can compensate the replicative fitness loss of IAV escape-variant. Here, we propose three additional mechanisms that contribute to the conservation of CD8 T cell epitopes of IAV. First, influenza-specific CD8 T cells may protect predominantly against severe pathology rather than infection and may only have a modest effect on transmission. Second, polymorphism of human MHC-I gene restricts the advantage of an escape-variant to only a small fraction of human population, who carry the relevant MHC-I alleles. Finally, infection with CD8 T cell-escapevariants may result in compensatory increase in the responses to other epitopes of IAV. A combination of population genetics and epidemiological models is used to examine how the interplay between these mechanisms affects the rate of invasion of IAV escape-variants. We conclude that the invasion of an escape-variant will be very slow with a timescale of decades or longer, even if the escape-variant does not have a replicative fitness loss. Our results suggest T cell-inducing vaccines may not engender the rapid evolution of IAV and serve as a foundation for future modeling works on the long-term effectiveness and impacts of T cell-inducing influenza vaccines. (Word count: 221)\n\nImportanceUniversal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear to which extent the T cell-inducing vaccines will select for viruses that escape the T cell responses. Our mathematical models suggest how the nature of CD8 T cell protection contributes to the conservation of the CD8 T cell epitopes of influenza A virus. Also, it points out the essential biological parameters and questions that need addressing by future experimental works. (Word count: 91)

immunology↗

bioRxiv2018

Exploring the impact of inoculum dose on host immunity and morbidity to inform model-based vaccine design

BackgroundVaccination is an effective method to protect against infectious diseases. An important consideration in any vaccine formulation is the inoculum dose, i.e., amount of antigen or live attenuated pathogen that is used. Higher levels generally lead to better stimulation of the immune response but might cause more severe side effects and allow for less population coverage in the presence of vaccine shortages. Determining the optimal amount of inoculum dose is an important component of rational vaccine design. A combination of mathematical models with experimental data can help determine the impact of the inoculum dose.\n\nMethodsWe designed mathematical models and fit them to data from influenza A virus (IAV) infection of mice and human parainfluenza virus (HPIV) of cotton rats at different inoculum doses. We used the model to predict the level of immune protection and morbidity for different inoculum doses and to explore what an optimal inoculum dose might be.\n\nResultsWe show how a framework that combines mathematical models with experimental data can be used to study the impact of inoculum dose on important outcomes such as immune protection and morbidity. We find that the impact of inoculum dose on immune protection and morbidity depends on the pathogen and both protection and morbidity do not always increase with increasing inoculum dose. An intermediate inoculum dose can provide the best balance between immune protection and morbidity, though this depends on the specific weighting of protection and morbidity.\n\nConclusionsOnce vaccine design goals are specified with required levels of protection and acceptable levels of morbidity, our proposed framework which combines data and models can help in the rational design of vaccines and determination of the optimal amount of inoculum.

systems biology↗