Immunological characteristics govern the transition of COVID-19 to endemicity.

We are currently faced with the question of how the severity of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may change in the years ahead. Our analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that infection-blocking immunity wanes rapidly but that disease-reducing immunity is long-lived. Our model, incorporating these components of immunity, recapitulates both the current severity of SARS-CoV-2 infection and the benign nature of HCoVs, suggesting that once the endemic phase is reached and primary exposure is in childhood, SARS-CoV-2 may be no more virulent than the common cold. We predict a different outcome for an emergent coronavirus that causes severe disease in children. These results reinforce the importance of behavioral containment during pandemic vaccine rollout, while prompting us to evaluate scenarios for continuing vaccination in the endemic phase.

Immune boosting explains regime-shifts in prevaccine-era pertussis dynamics.

Understanding the biological mechanisms underlying episodic outbreaks of infectious diseases is one of mathematical epidemiology's major goals. Historic records are an invaluable source of information in this enterprise. Pertussis (whooping cough) is a re-emerging infection whose intermittent bouts of large multiannual epidemics interspersed between periods of smaller-amplitude cycles remain an enigma. It has been suggested that recent increases in pertussis incidence and shifts in the age-distribution of cases may be due to diminished natural immune boosting. Here we show that a model that incorporates this mechanism can account for a unique set of pre-vaccine-era data from Copenhagen. Under this model, immune boosting induces transient bursts of large amplitude outbreaks. In the face of mass vaccination, the boosting model predicts larger and more frequent outbreaks than do models with permanent or passively-waning immunity. Our results emphasize the importance of understanding the mechanisms responsible for maintaining immune memory for pertussis epidemiology.

Resolving pertussis immunity and vaccine effectiveness using incidence time series.

Resolving the long-term, population-level consequence of vaccine-induced immunity to pertussis is a key challenge for control strategies and vaccine development. Controlled vaccine efficacy studies provide invaluable information; however, they are limited in scope by their sample size and follow-up duration. Long-term time series of incidence data collected by public health institutions provide insight at a broader scale, especially when the data are spatially explicit and age stratified. By using modern ecological and statistical methodolgies, which are reviewed in this paper, new insights into the duration of transmission-blocking immunity and the age-specific patterns of transmission can be gained. Recent advances in computing power and statistical software development will increasingly make these methods available to public health practitioners, vaccine developers and academics alike.

Self-boosting vaccines and their implications for herd immunity.

Advances in vaccine technology over the past two centuries have facilitated far-reaching impact in the control of many infections, and today's emerging vaccines could likewise open new opportunities in the control of several diseases. Here we consider the potential, population-level effects of a particular class of emerging vaccines that use specific viral vectors to establish long-term, intermittent antigen presentation within a vaccinated host: in essence, "self-boosting" vaccines. In particular, we use mathematical models to explore the potential role of such vaccines in situations where current immunization raises only relatively short-lived protection. Vaccination programs in such cases are generally limited in their ability to raise lasting herd immunity. Moreover, in certain cases mass vaccination can have the counterproductive effect of allowing an increase in severe disease, through reducing opportunities for immunity to be boosted through natural exposure to infection. Such dynamics have been proposed, for example, in relation to pertussis and varicella-zoster virus. In this context we show how self-boosting vaccines could open qualitatively new opportunities, for example by broadening the effective duration of herd immunity that can be achieved with currently used immunogens. At intermediate rates of self-boosting, these vaccines also alleviate the potential counterproductive effects of mass vaccination, through compensating for losses in natural boosting. Importantly, however, we also show how sufficiently high boosting rates may introduce a new regime of unintended consequences, wherein the unvaccinated bear an increased disease burden. Finally, we discuss important caveats and data needs arising from this work.

Lack of cross-protection against Bordetella holmesii after pertussis vaccination.

Bordetella holmesii, a species closely related to B. pertussis, has been reported sporadically as a cause of whooping cough-like symptoms. To investigate whether B. pertussis-induced immunity is protective against infection with B. holmesii, we conducted an analysis using 11 human respiratory B. holmesii isolates collected during 2005-2009 from a highly B. pertussis-vaccinated population in Massachusetts. Neither whole-cell (wP) nor acellular (aP) B. pertussis vaccination conferred protection against these B. holmesii isolates in mice. Although T-cell responses induced by wP or aP cross-reacted with B. holmesii, vaccine-induced antibodies failed to efficiently bind B. holmesii. B. holmesii-specific antibodies provided in addition to wP were sufficient to rapidly reduce B. holmesii numbers in mouse lungs. Our findings suggest the established presence of B. holmesii in Massachusetts and that failure to induce cross-reactive antibodies may explain poor vaccine-induced cross-protection.

Short-lived immunity against pertussis, age-specific routes of transmission, and the utility of a teenage booster vaccine.

BACKGROUND: Pertussis incidence has been increasing for the past two decades in Norway, as in much of the highly vaccinated world. The greatest increase is in teenagers, although the most severe cases occur in infants. A teenage booster is recommended globally, largely with the aim of reducing infant incidence. However few countries have implemented the booster, and almost no data have been published on its utility in preventing infant cases. We aim to assess the duration of vaccine-induced immunity, and the possibility for a teenage-booster vaccine to protect infants in Norway. METHODS AND FINDINGS: We used a unique data set that merged case reports with a national vaccine registry from Norway, 1996-2010, to assess age- and cohort-specific hazards of infection. We also developed and implemented a likelihood-based method for estimating the duration of immunity, taking into account age-contact data relevant for pertussis transmission. The risk of infection in thirteen-year olds increased nearly four-fold, however the hazard in infants did not significantly change. The seasonality of cases in pre-school-aged children differed from that of school-aged children. The introduction of a childhood booster vaccine provided indirect protection for unvaccinated members of the cohort, but little protection to neighboring cohorts. Additionally, we found evidence for increasingly rapid infection after three doses of vaccine, potentially caused by significant and heterogeneous loss of immunity. An estimated 15% of vaccinated individuals lost their immunity within five years after vaccination. CONCLUSIONS: Immunity induced by the acellular pertussis vaccine prevents both disease and transmission, but is short-lived and heterogeneous. The age-mixing patterns lead to little contact between teenagers and infants. Therefore, while a teenage booster vaccine campaign would likely provide strong protection for cohorts of teenagers, it would provide little protection for infants.

Natural immune boosting in pertussis dynamics and the potential for long-term vaccine failure.

Incidence of whooping cough, unlike many other childhood diseases for which there is an efficacious vaccine, has been increasing over the past twenty years despite high levels of vaccine coverage. Its reemergence has been particularly noticeable among teenagers and adults. Many hypotheses have been put forward to explain these two patterns, but parsimonious reconciliation of clinical data on the limited duration of immunity with both pre- and postvaccine era age-specific incidence remains a challenge. We consider the immunologically relevant, yet epidemiologically largely neglected, possibility that a primed immune system can respond to a lower dose of antigen than a naive one. We hypothesize that during the prevaccine era teenagers' and adults' primed immunity was frequently boosted by reexposure, so maintaining herd immunity in the face of potentially eroding individual immunity. In contrast, low pathogen circulation in the current era, except during epidemic outbreaks, allows immunity to be lost before reexposure occurs. We develop and analyze an age-structured model that encapsulates this hypothesis. We find that immune boosting must be more easily triggered than primary infection to account for age-incidence data. We make age-specific and dynamical predictions through bifurcation analysis and simulation. The boosting model proposed here parsimoniously captures four key features of pertussis data from highly vaccinated countries: (i) the shift in age-specific incidence, (ii) reemergence with high vaccine coverage, (iii) the possibility for cyclic dynamics in the pre- and postvaccine eras, and (iv) the apparent shift from susceptible-infectious-recovered (SIR)-like to susceptible-infectious-recovered-susceptible (SIRS)-like phenomenology of infection and immunity to Bordetella pertussis.

Directly transmitted viral diseases: modeling the dynamics of transmission.

A key hurdle in understanding the spread and control of infectious diseases is to capture appropriately the dynamics of pathogen transmission. As people and goods travel increasingly rapidly around the world, so do pathogens; we must be prepared to understand their spread, in terms of the contact network between hosts, viral life history and within-host dynamics. This will require collaborative work that takes into account viral life history, strategy and evolution, and host genetics, demographics and immunodynamics. Mathematical models are a useful tool for integrating the data and analyses from diverse fields that contribute to our understanding of viral transmission dynamics in heterogeneous host populations.