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The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with presymptomatic, symptomatic, and asymptomatic infections, the reopening of societies and the control of virus spread will be facilitated by robust population screening, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are too low to detect, followed by exponential viral growth, leading to peak viral load and infectiousness and ending with declining titers and clearance. Given the pattern of viral load kinetics, we model the effectiveness of repeated population screening considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective screening depends largely on frequency of testing and speed of reporting and is only marginally improved by high test sensitivity. We therefore conclude that screening should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with pre-symptomatic, symptomatic, and asymptomatic infections, the re-opening of societies and the control of virus spread will be facilitated by robust surveillance, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are usually too low to detect, followed by an exponential growth of virus, leading to a peak viral load and infectiousness, and ending with declining viral levels and clearance. Given the pattern of viral load kinetics, we model surveillance effectiveness considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective surveillance, including time to first detection and outbreak control, depends largely on frequency of testing and the speed of reporting, and is only marginally improved by high test sensitivity. We therefore conclude that surveillance should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.

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Measles virus is directly responsible for more than 100,000 deaths yearly. Epidemiological studies have associated measles with increased morbidity and mortality for years after infection, but the reasons why are poorly understood. Measles virus infects immune cells, causing acute immune suppression. To identify and quantify long-term effects of measles on the immune system, we used VirScan, an assay that tracks antibodies to thousands of pathogen epitopes in blood. We studied 77 unvaccinated children before and 2 months after natural measles virus infection. Measles caused elimination of 11 to 73% of the antibody repertoire across individuals. Recovery of antibodies was detected after natural reexposure to pathogens. Notably, these immune system effects were not observed in infants vaccinated against MMR (measles, mumps, and rubella), but were confirmed in measles-infected macaques. The reduction in humoral immune memory after measles infection generates potential vulnerability to future infections, underscoring the need for widespread vaccination.

Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre-and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity.Measles vaccines were introduced 50 years ago and were followed by striking reductions in child morbidity and mortality (1, 2). Measles control is now recognized as one of the most successful public health interventions ever undertaken (3). Despite this, in many countries vaccination targets remain unmet, and measles continues to take hundreds of thousands of lives each year (3). Even where control has been successful, vaccine hesitancy threatens the gains that have been made (1, 4). The introduction of mass measles vaccination has reduced childhood mortality by 30 to 50% in resource-poor countries (5-8) and by up to 90% in the most impoverished populations (9, 10). The observed benefits cannot be explained by the prevention of primary measles virus (MV) infections alone (11,12), and they remain a central mystery (13). Author ManuscriptAuthor Manuscript Author Manuscript Author ManuscriptMV infection is typified by a profound, but generally assumed to be transient, immunosuppression that renders hosts more susceptible to other pathogens (14-17). Thus, contemporaneous reductions in nonmeasles mortality after vaccination are expected. However, reductions in infectious disease mortality after measles vaccination can last throughout the first 5 years of life (5-10), which is much longer than anticipated by transient immunosuppression, which is generally considered to last for weeks to months (16,17).Proposed mechanisms for a nonspecific beneficial effect of measles vaccination range from suggestions that live vaccines may directly stimulate cross-reactive T cell responses or that they may train innate immunity to take on memory-like phenotypes (13,(18)(19)(20)(21) (25), the authors hypothesized that rapid expansions of predominantly measlesspecific B and T lymphocytes masked an ablated memory-cell population (17). In other words, MV infection replaced the previous memory cell repertoire with MV-specific lymphocytes, resulting in "immune amnesia" (17) to nonmeasles pathogens. Previous investigations of virus-induced memory-cell depletion suggest that recovery requires restimulation, either directly or via cross-rea...

The future trajectory of the Covid-19 pandemic hinges on the dynamics of adaptive immunity against SARS-CoV2; however, salient features of the immune response elicited by natural infection or vaccination are still uncertain. We use simple epidemiological models to explore estimates for the magnitude and timing of future Covid-19 cases given different protective efficacy and duration of the adaptive immune response to SARS-CoV-2, as well as its interaction with vaccines and nonpharmaceutical interventions. We find that variations in the immune response to primary SARS-CoV-2 infections and a potential vaccine can lead to dramatically different immune landscapes and burdens of critically severe cases, ranging from sustained epidemics to near elimination. Our findings illustrate likely complexities in future Covid-19 dynamics, and highlight the importance of immunological characterization beyond the measurement of active infections for adequately projecting the immune landscape generated by SARS-CoV-2 infections.