Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality

Abstract

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...

Resurgence of Vaccine-Preventable Diseases in the United States: Anesthetic and Critical Care Implications

“…Immune system function is depressed for months and possibly years because of measles infection, leading to an increased chance of secondary infection. 44,49 After exposure and an average incubation period of approximately 10 days, nonspecific symptoms of fever, cough, coryza, and conjunctivitis appear, followed by a characteristic truncal and facial rash 2 to 4 days later. Patients can be infectious before the appearance of the rash.…”

Measles Vaccination Associated With Lower Mortality Risk From Other Childhood Infections

“…A new study suggests that the measles virus may result in a longer-lasting "immune-amnesia" that makes it harder for children to fight off other diseases for 2 to 3 years (Mina et al, 2015). According to the researchers, these results provide additional evidence of the public health benefits of the measles vaccine.…”

A Structurally Unresolved Head Segment of Defined Length Favors Proper Measles Virus Hemagglutinin Tetramerization and Efficient Membrane Fusion Triggering

“…CHO cells (2 ϫ 10 5 in 12-well plates) were transfected with 0.3 g each of the H and F expression plasmids and one of the dual-split-reporter luciferase expression plasmids (DSP [1][2][3][4][5][6][7] , a kind gift of Z. Matsuda). As a control, only the H or the F plasmid was cotransfected with DSP [1][2][3][4][5][6][7] . Vero cells (4 ϫ 10 5 in 6-well plates) were transfected with 1.5 g of the other dual-split-reporter plasmid (DSP 8 -11 ).…”

“…Relaxed vaccination discipline has favored measles reemergence in Europe and North America, which now report costly epidemics: in 2013 the number of measles cases in the United States was triple that in previous years, in 2014 it was about 10-fold higher (3)(4)(5)(6), and in 2015 a Disneyland-originated outbreak reminded the world of the immediate benefits of high measles vaccination coverage. Moreover, a recent retrospective study of the consequences of the introduction of measles vaccination 50 years ago indicated that elimination of measles-induced immune suppression significantly reduced child death due to opportunistic infections (7).…”