Biology subjects

Antia, R.

Publications and source records attributed to Antia, R..

18 recordsLinked to original sources

bioRxiv2026

CD8+ T cells and Humoral Immunity Influence the Development of Antibody-Dependent Enhancement: Implications for Vaccine Design

Dengue virus (DENV) infection is a major and growing global health threat. The development of a safe and effective vaccine regardless of prior dengue immunity remains an unmet need. Virus-specific antibodies typically limit viral replication. In contrast, low-to-intermediate dengue-specific antibody titers can enhance viral replication and increase disease severity--a phenomenon known as antibody-dependent enhancement (ADE). ADE complicates dengue vaccine development; signals of ADE were observed in the CYD-TDV (Dengvaxia) vaccine trials but have not yet been reported for trials of TAK-003 (Qdenga). To better understand how prior immunity influences dengue infection outcomes, we developed a mechanistic within-host model of acute dengue infection dynamics that incorporates both humoral immunity and CD8+ T cells. Model simulations predict that severe disease is most likely when dengue-specific antibody titers are intermediate and dengue-specific CD8+ T-cell immunity is low at the time of infection. In our simulations, increasing pre-infection levels of CD8+ T-cell immunity reduces disease severity in a dose-dependent manner and can mitigate ADE. Our results suggest a mechanistic interaction between antibody levels and CD8+ T-cell immunity that may influence whether enhanced viral replication leads to severe disease. The model provides a possible explanation for why ADE is frequently observed in infections of nonhuman primates following passive antibody transfer, yet is less common during secondary infections in humans with memory CD8+ T cells. These findings may help interpret differences in reported clinical outcomes of dengue vaccine trials and highlight the importance of considering CD8+ T-cell responses in the design of future dengue vaccines. ImportanceVaccines, including those against dengue viruses, are typically designed to elicit humoral (antibody-mediated) immunity, as antibody titers are commonly used as primary correlates of protection. Because CD8+ T-cell responses are not usually primary correlates and are more challenging to measure, they have received comparatively less attention. For viruses such as dengue, however, antibodies can exacerbate disease severity through antibody-dependent enhancement (ADE), underscoring the need to understand how humoral and cellular immunity interact. Here, we present a mechanistic model showing that severe dengue disease arises not only from low-to-intermediate antibody levels but also from insufficient CD8+ T-cell immunity at the time of infection. The model predicts that CD8+ T-cell responses can mitigate ADE-associated pathology and may help explain the differing levels of protection observed for CYD-TDV and TAK-003 vaccines. These findings suggest that evaluating CD8+ T-cell responses alongside antibody titers may be important for assessing vaccine safety and protection.

immunology↗

bioRxiv2026

Preventing Disease Emergence Following Eradication: Application to Mpox

We use simple mathematical models to explore the factors that influence the evolutionary emergence of mpox to a pathogen capable of sustained human to human transmission that poses a global threat. Smallpox eradication followed by the discontinuation of immunization with vaccinia has led to a decline in the level of population immunity against related poxviruses such as mpox. This decline in immunity results in an increase in both the number of spillovers and the extent of human to human transmission. We find that increases in transmissibility of mpox between humans have a much greater effect on the probability of evolutionary emergence compared with increases in the number of zoonotic spillovers. We suggest that while mpox only needs to have a reproductive number slightly greater than one to become endemic, subsequent adaptation is likely to further increase its transmissibility in the human population. As a consequence a much higher level of vaccination (or other intervention) is needed to control the pathogen after its evolutionary emergence compared with what is needed to prevent it from emerging in the first place.

evolutionary biology↗

bioRxiv2025

Density dependence affects population recovery following an epidemic

Current epidemiological models for the regulation of host populations by pathogens suggest that the reduction in the host population is largest shortly after the epidemic phase and that the host population partly recovers in the subsequent approach to endemicity. We find that this conventional view is not robust to a simple, biologically motivated addition: density-dependent population regulation (homeostasis). While rapid homeostasis typically enables a population rebound after the initial population suppression (the conventional view), we show that weak homeostasis can result in the opposite --- greater population suppression during the endemic phase compared to the initial epidemic. The effect of homeostasis, which is a property of the host population, can be substantial. This finding complicates the prediction of long term outcomes of population suppression by pathogens but not of short term outcomes.

ecology↗

bioRxiv2025

Short and long term suppression of host populations by novel pathogens

Current theory for the regulation of host populations by pathogens suggests that a high level of suppression during the initial epidemic phase will be followed by a population rebound with decreased virulence due to pathogen and host evolution, and the extent of host suppression increases with increasing pathogen transmissibility (R0) and virulence. Using simple epidemiological models, we explore the effect of two factors on short- and long-term suppression: the strength of density-dependent population regulation (homeostasis) and maternal antibodies. We showed previously that, in the absence of maternal antibodies, the strength of homeostasis can greatly effect long term population suppression. Here we find that maternal antibodies can significantly reduce suppression of the host population if they attenuate rather than block infections, but then only for rapid homeostasis. A higher R0 can result in lower suppression, and the average virulence can decline over time without any (genetic) evolution. Our results suggest the need for a nuanced view of long-term suppression by a new pathogen, with the outcome sensitive to many details even in the absence of evolution.

ecology↗

bioRxiv2025

Quantifying the role of pre-existing tissue resident cellular immunity in limiting respiratory virus transmission

Viral transmission from infected donors to uninfected recipients is the key event underlying the spread of viral pathogens at the level of a host population. Successful viral transmission from a donor to a recipient depends on several factors including the infectiousness of the donor. Donor infectiousness in turn can depend on the viral kinetics and viral load of the donor, donor behavior and symptoms, and donor immunity. Here, we use a mouse model of murine respirovirus (otherwise known as Sendai virus SeV) infection to quantitatively explore donor determinants of respiratory virus transmission. The experimental transmission studies we analyze are specifically designed to address the effect that pre-existing donor immunity may have on transmission potential by studying SeV transmission from both immunized and control (placebo-immunized) donors to naive recipients. We specifically focus on the impact of tissue resident memory (TRM) CD8 T cells on donor transmission potential by considering immunization strategies that primarily generate CD8 T cell immunity. Through quantitative analyses of these experiments, we find that pre-existing CD8 TRMs act to reduce donor transmission potential. This reduction can be in part explained by a reduction in total infection load in immunized donors. However, even once differences in infection load between immunized and control donors are accounted for, immunized donors still have reduced infectiousness relative to control donors. We explore possible reasons for this unexpected pattern using a mathematical model that integrates within-host viral dynamics and between-host transmission occurrences. Analysis of model simulations, along with observations from knock-out experiments, suggests that interferon gamma (IFN-{gamma}) may be partly responsible for the observed differences in infectiousness between control and pre-immune donors. Future experimental transmission studies should consider measuring IFN-{gamma} levels when interpreting transmission outcomes in the context of host immunity.

immunology↗

bioRxiv2024

Waning immunity drives respiratory virus evolution and reinfection

Reinfections with respiratory viruses such as influenza viruses and coronaviruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with a heterologous, antigenically different strain. As such, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect fully immune hosts. Invasion can occur even when the variants immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should replace the wild-type, and as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.

evolutionary biology↗

bioRxiv2022

Memory CD4 T cell subset organization in the female reproductive tract is regulated via the menstrual cycle through CCR5 signaling

Despite their importance for immunity against sexually transmitted infections (STIs), the composition of the female reproductive tract (FRT) memory CD4 T cell population in response to changes in the local tissue environment during the menstrual cycle remains poorly defined. Here we show that across humans, non-human primates (NHP), and mice, FRT CD4 T cells comprise distinct subsets corresponding to migratory memory (TMM) and resident memory (TRM) cells. TMM display tissue-itinerant trafficking characteristics, restricted FRT tissue distribution, with distinct transcriptional properties and effector responses to infection. CD4 T cell subset fluctuations synchronized with cycle-driven proinflammatory changes within the local tissue environment and oral administration of a CCR5 antagonist inhibited cycle phase-specific migratory T cell surveillance. This study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of memory T cell defense at the site of STI exposure. SummaryThe menstrual cycle regulates memory T cell surveillance.

immunology↗

bioRxiv2022

Modeling suggests that multiple immunizations or infections will reveal the benefits of updating SARS-CoV-2 vaccines

When should vaccines to evolving pathogens such as SARS-CoV-2 be updated? Our computational models address this focusing on updating SARS-CoV-2 vaccines to the currently circulating Omicron variant. Current studies typically compare the antibody titers to the new variant following a single dose of the original-vaccine versus the updated-vaccine in previously immunized individuals. These studies find that the updated-vaccine does not induce higher titers to the vaccine-variant compared with the original-vaccine, suggesting that updating may not be needed. Our models recapitulate this observation but suggest that vaccination with the updated-vaccine generates qualitatively different humoral immunity, a small fraction of which is specific for unique epitopes to the new variant. Our simulations suggest that these new variant-specific responses could dominate following subsequent vaccination or infection with either the currently circulating or future variants. We suggest a two-dose strategy for determining if the vaccine needs updating and for vaccinating high-risk individuals.

immunology↗

bioRxiv2021

Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency and division rates of YFV-specific memory CD8 T cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.001 per day, ~double estimates for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically. Author summaryImmunological memory, generated in response to infection or vaccination, may provide complete or partial protection from antigenically similar infections for the lifetime. Memory CD8 T cells are important players in protection from secondary viral infections but quantitative understanding of their dynamics in humans is limited. We analyze data from two studies where immunization with the yellow fever virus vaccine (YFV-17D) generates a mild acute infection and long-term memory. We find that: (i) the division rate of YFV-17D-specific CD8 T cells drops and stabilizes at ~ 0.1% per day during the first year following vaccination whereas the death rate declines more gradually, and (ii) the number of these cells declines approximately in accordance with a power law ({propto}time-0.82) for at least several decades following vaccination.

immunology↗

bioRxiv2020

Vaccination reshapes the virus-specific T cell repertoire in unexposed adults

How baseline T cell characteristics impact human T cell responses to novel pathogens remains unknown. Here, we address this question by studying the CD4+ T cell response in unexposed individuals to live attenuated yellow fever virus (YFV) vaccine. We quantified virus-specific population dynamics over time using class II peptide-MHC tetramers. Our data revealed that, even in the absence of known viral exposure, memory phenotype T cells were found in the majority of virus-specific precursors in healthy adults. Pre-existing memory T cells can be divided into two groups; abundant pre-vaccine populations that underwent limited overall expansion and rare cells that generated naive-like responses and preferentially contributed to the memory repertoire after vaccination. Single cell T cell receptor (TCR) sequencing was used to track the evolution of immune responses to different epitopes and showed an association between preservation of unexpanded TCRs before exposure and the robustness of post-vaccine responses. Instead of a further increase in pre-established TCR clones, vaccination boosted the representation of rare TCRs. Thus, vaccine restructures the abundance and clonal hierarchy of virus-specific T cells. Our results link T cell precursor states to post-exposure responses, identifying peripheral education of virus-specific repertoire as a key component of effective vaccination. {circ}YFV-specific precursors contain abundant memory phenotype cells in healthy adults. {circ}Precursor frequency and phenotype are linked to post-immune response. {circ}Vaccination recruits rare virus-specific populations. {circ}Vaccination overrides pre-established clonal hierarchy

immunology↗

bioRxiv2020

Using directed attenuation to enhance vaccine immunity

Many viral infections can be prevented by immunizing with live, attenuated vaccines. Early methods of attenuation were hit-and-miss, and these are now much improved by genetic engineering. But even current attenuation methods operate on the principle of genetic harm, reducing the viruss ability to grow, which in turn limits the host immune response below that of infection by wild-type. We use mathematical models of the dynamics of virus and its control by innate and adaptive immunity to explore the tradeoff between attenuation of virus growth and the generation of immunity. Our analysis suggests that directed attenuation that disables key viral defenses against the host immune responses may attenuate viral growth without compromising, and potentially even enhancing the generation of immunity. We explore which immune evasion pathways should be attenuated and how attenuating multiple pathways could lead to robust attenuation of pathology with enhancement of immunity. Author summaryLive attenuated virus vaccines are among the most effective interventions to combat viral infections. Historically, the mechanism of attenuation has been one of genetically reduced viral growth rate, often achieved by adapting the virus to grow in a novel cells. More recent attenuation methods use genetic engineering but also are thought to impair viral growth rate. These classical attenuations typically result in a tradeoff whereby attenuation depresses the within-host viral load and pathology (which is beneficial to vaccine design), but reduces immunity (which is not beneficial). We use models to explore ways of directing the attenuation of a virus to avoid this tradeoff. We show that directed attenuation by interfering with (some) viral immune-evasion pathways can yield a mild infection but elicit higher levels of immunity than of the wild-type virus.

immunology↗

bioRxiv2020

Quantifying memory CD8 T cell-mediated immune pressure on influenza A virus infection in vivo

The conservation of T cell epitopes in human influenza A virus has prompted the development of T cell-inducing influenza vaccines. However, the selection pressure mediated by memory CD8 T cells upon influenza virus has not been directly measured. Using a droplet digital PCR technique to distinguish wild-type and an epitope-mutant PR8 influenza viruses in vivo, this study quantifies the viral replicative fitness of a CD8 T cell-escaping mutation in the immunodominant influenza NP366-374 epitope in C57BL/6 (B6) mice under different settings of cellular immunity. Although this mutation does not result in a viral fitness defect in vitro or during the early stages of in vivo infection in naive B6 mice, it does confer a moderate but consistent advantage to the mutant virus following heterosubtypic challenge of HKx31-immunized mice. In addition, this advantage was maintained under increased MHC diversity but became more substantial when the breadth of epitope recognition is limited. Finally, we showed that lung-resident, but not circulating, memory CD8 T cells are the primary source of cellular immune pressure early during infection, prior to the induction of a secondary effector T cell response. Integrating the data with an established modeling framework, we show that the relatively modest immune pressure mediated by memory CD8 T cells is one of the important factors responsible for the conservation of CD8 T cell epitopes in influenza A viruses that circulate among humans. Thus, a T cell-inducing vaccine that generates lung-resident memory CD8 T cells covering a sufficient breadth of epitopes may transiently protect against severe pathology without driving the virus to rapidly evolve and escape. Author SummarySince the historic Spanish flu in 1918, influenza has caused several pandemics and become an important public health concern. The inactivated vaccines routinely used attempt to boost antibodies, which may not be as effective when antigenic mismatch happens and could drive the virus to evolve and escape due to their high immune pressure. In contrast, the ability of influenza-specific T cells to reduce pathology and the conservation of T-cell epitopes across subtypes have shed light on the development of universal vaccines. In this study, we assessed the CD8 T cell-mediated selection pressure on influenza virus in mouse using a digital PCR technique. Within mice that have influenza-specific systemic and lung-resident memory CD8 T cells established, we found the advantage conferred by an escaping mutation in one of the immunodominant epitopes is around 25%. This advantage becomes much greater when the cellular immunity focuses on the focal epitope, while it is delayed when only systemic cellular immunity is established. Combining the data with our previous modeling work, we conclude that the small selection pressure imposed by CD8 T cells can explain the overall conservation of CD8 T cell epitopes of influenza A virus in addition to functional constraint.

immunology↗

bioRxiv2019

Recombinant vector vaccines and within-host evolution

Many recombinant vector vaccines are capable of replication within the host. They consist of a fully competent vector backbone engineered to express an antigen from a foreign transgene. From the perspective of viral replication, the transgene is not only dispensable but may even be intrinsically detrimental. Thus vaccine revertants that delete the transgene may evolve to dominate the within-host population and in doing so reduce the antigenicity of the vaccine. We apply mathematical and computational models to study this process, including the dynamics of vaccine and revertant growth plus the dynamics of innate and adaptive immunity. Although the selective basis of vaccine evolution is easy to comprehend, the immunological consequences are not. One complication is that, despite possible fitness differences between vaccine and revertant, the opportunity for vaccine evolution is limited by the short period of growth before the viral population is cleared. Even less obvious, revertant per se does not interfere with immunity to vaccine except as the revertant suppresses vaccine abundance; the magnitude of this interference depends on mechanisms and timing of viral suppression. Adaptive immunity targeting the foreign antigen is also a possible basis of vaccine inferiority, but it is not worsened by vaccine evolution. Overall, we find that within-host vaccine evolution can sometimes matter to the adaptive immune response targeting the foreign antigen, but even when it does matter, simple principles of vaccine design and the control of inoculum composition can largely mitigate the effects. Author SummaryRecombinant vector vaccines are live replicating viruses that are engineered to carry extra genes derived from a pathogen - and these produce proteins against which we want to generate immunity. These genes may evolve to be lost during the course of replication within an individual, and there is a concern that this can severely limit the vaccines efficacy. The dynamics of this process are studied here with mathematical models. The potential for vaccine evolution is somewhat reduced by the short-term growth of the vaccine population before it is suppressed by the immune response. Even when within-host evolution can be a problem, the models show that increasing the vaccine inoculum size or ensuring that the inoculum is mostly pure vaccine can largely avoid the loss of immunity arising from evolution.

evolutionary biology↗

bioRxiv2019

A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections

Some viral infections culminate in very different outcomes in different individuals. They can be rapidly cleared in some, cause persistent infection in others, and mortality from immunopathology in yet others. The conventional view is that the different outcomes arise as a consequence of the complex interactions between a large number of different factors (virus, different immune cells and cytokines). Here, we identify a simple dynamical motif comprising the essential interactions between antigens and CD8 T cells and posit it as predominantly determining the outcomes. Antigen can activate CD8 T cells, which in turn can kill infected cells. Sustained antigen stimulation, however, can cause CD8 T cell exhaustion, compromising effector function. Using mathematical modelling, we show that the motif comprising these interactions recapitulates all the outcomes observed. The motif presents a new conceptual framework to understand the variable outcomes of infection. It also explains a number of confounding experimental observations, including the variation in outcomes with the viral inoculum size, the evolutionary advantage of exhaustion in preventing lethal pathology, the ability of NK cells to act as rheostats tuning outcomes, and the role of the innate immune response in the spontaneous clearance of hepatitis C. Interventions that modulate the interactions in the motif may present novel routes to clear persistent infections or limit immunopathology.

immunology↗

bioRxiv2019

Incomplete influenza A virus genomes are abundant but readily complemented during spatially structured viral spread

Viral genomes comprising multiple distinct RNA segments can undergo genetic exchange through reassortment, a process that facilitates viral evolution and can have major epidemiological consequences. Segmentation also allows the replication of incomplete viral genomes (IVGs), however, and evidence suggests that IVGs occur frequently for influenza A viruses. Here we quantified the frequency of IVGs using a novel single cell assay and then examined their implications for viral fitness. We found that each segment of influenza A/Panama/2007/99 (H3N2) virus has only a 58% probability of being present in a cell infected with a single virion. These observed frequencies accurately account for the abundant reassortment seen in co-infection, and suggest that an average of 3.7 particles are required for replication of a full viral genome in a cell. This dependence on multiple infection is predicted to decrease infectivity and to slow viral propagation in a well-mixed system. Importantly, however, modeling of spatially structured viral growth predicted that the need for complementation is met more readily when secondary spread occurs locally. This expectation was supported by experimental infections in which the level spatial structure was manipulated. Furthermore, a virus engineered to be entirely dependent on co-infection to replicate in vivo was found to grow robustly in guinea pigs, suggesting that coinfection is sufficiently common in vivo to support propagation of IVGs. The infectivity of this mutant virus was, however, reduced 815-fold relative wild-type and the mutant virus did not transmit to contacts. Thus, while incomplete genomes augment reassortment and contribute to within-host spread, the existence of rare complete IAV genomes may be critical for transmission to new hosts.

microbiology↗

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↗