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How sex and age affect immune responses, susceptibility to infections, and response to vaccination

Carmen Giefing‐Kröll, Peter Berger, Günter Lepperdinger and 1 more

Aging Cell · 2015 · Review · CC BY

doi:10.1111/acel.12326

Abstract

Summary Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age‐related changes, both the immune and the endocrine system exhibit significant sex‐specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune‐privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

A paradoxical situation between aging male and female is evident in particular regarding health status and the corresponding survival rates (Oksuzyan et al., ). Women exhibit significantly higher life expectancies, while frequently experiencing disabilities earlier in life (Van Oyen et al., ). Independent of age, death rates due to cancer, heart disease, accidents, influenza, or pneumonia are significantly higher in men (Austad, ). Here, major contributors appear to be lifestyle differences: smoking accounts for ∼60% of gender-specific mortality in Europe, alcohol abuse for ∼30% (McCartney et al., ), followed by risk-taking and seeking and complying with medical therapies (Oksuzyan et al., ). Besides that, major biological determinants of the sexual dimorphism in longevity are X chromosome diploidy, as well as distinct differences in immune and hormone responses (Vina et al.,; Austad,; Oksuzyan et al., ), the latter both showing consistent changes with aging.

Women carry two X chromosomes. The X chromosome expresses several genes implicated in immunological processes, such as Toll-like receptors, multiple cytokine receptors, genes involved in T-cell and B-cell activity, and transcriptional and translational regulatory factors (Fish, ), while in turn the Y chromosome encodes for a number of inflammatory pathway genes, which are exclusively expressed in men (Flanagan, ). Most alleles on one X chromosome are randomly silenced during X chromosome inactivation already during embryogenesis. Polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles may offer additional advantages to women during host responses, in particular by providing a more adaptive and balanced cellular machinery during innate immune responses (Spolarics,; Libert et al., ). Here, we therefore reviewed the current consistent knowledge on aging and sex-dimorphic susceptibility to infectious diseases and vaccination response in the context of changing levels of sex steroid hormones.

Sexual dimorphic susceptibility to infectious diseases

Sex-specific infection and mortality rates have been documented in humans (Table1). This sexual dimorphism commences already during intrauterine development, for example, a male fetus experiencing a chronic inflammatory environment primarily being induced by the maternal immune system in the male placenta via decidual sites yet also likely due to a higher gestational infection rate of male placenta [(Goldenberg et al., ), reviewed in detail in (Clifton, )]. Later in life very probably due to socioeconomic behavior, such as higher pathogen exposure during agricultural or occupational activities, men are more susceptible to many infections caused by viruses, bacteria, parasites, and fungi. They are significantly more predisposed especially to environmental and vector-borne diseases such as leptospirosis (3.5- to 4-fold increased incidence), schistosomiasis (1.5-fold), brucellosis, or rabies (Corbel,; Guerra-Silveira & Abad-Franch, ). Albeit at comparable exposure levels, men exhibit higher incidence rates for leishmaniasis (2.5- to 3.5-fold increased incidence), pulmonary tuberculosis (2- to 3-fold), and hepatitis A (1.4-fold), again surmising the role of distinct biological differences (Guerra-Silveira & Abad-Franch, ). Similarly, premenopausal women succumb less often to meningococcal or pneumococcal infections. Testosterone exerts immune suppressive effects thereby increasing the severity of malaria, leishmaniasis, amebiasis, and tuberculosis, while at the same time supporting the clearance of toxoplasmosis (Bernin & Lotter,; Nhamoyebonde & Leslie, ).

In contrast, sexually transmitted diseases occur more frequently and severely in women during their reproductive years supposedly due to behavior, sex-related mechanisms in reproduction and sex-specific steroid hormone levels (Rakasz & Lynch, ). The susceptibility to certain genital tract infections is further increased when applying oral contraceptives (Mohllajee et al., ). Once infected with HIV, progression toward AIDS was found to be faster in women (Meier et al.,; Addo & Altfeld, ). Variant incidence rates and severity regarding herpes zoster in women remain controversial (Thomas & Hall,; Yawn & Gilden, ). Influenza shows a sex-biased incidence, yet besides elusive countrywise discrepancies, also strainwise differences remain to be resolved. Notably, however, men seem to be more affected by seasonal influenza (Lozano et al.,; Quandelacy et al., ), whereas premenopausal women succumb more often to pandemic strains (Serfung et al.,; Klein et al.,,; Klein et al., ). In cases of measles, toxoplasmosis, dengue, or hantavirus infections, incidence rates are not sex-biased. However, disease outcome was significantly worse in women, especially during reproductive years suggesting a decisive role for gonadal sex hormones (Garenne,; Roberts et al.,; Klein et al.,; Guerra-Silveira & Abad-Franch, ). In women, elevated induction of pro-inflammatory cytokines and chemokines correlated with higher morbidity and mortality due to influenza infections (Klein et al., ). Again in women with ‘Escherichia-coli-O104:H4-associated-hemolytic-uremic-syndrome’, the humoral response was found stronger leading to detrimental effects most likely due to the overwhelming production of pathogenic antibodies (Frank et al.,; Greinacher et al., ).

It is well known that the aging process affects sexual dimorphism regarding immunocompetence and disease susceptibility. Aging women lose their immunological advantage. Particularly, they show increased susceptibility and mortality with respect to hepatitis, meningococcal, or pneumococcal infections (Table1). Protective effects of estrogen are thought to enable premenopausal women to clear the hepatitis C virus and thus progress slower to the disease than age-matched men. After menopause, these sex differences were lost and treatment efficacy was severely decreased (Khattab & Eslam,; Baden et al., ). Notably, however, immune-pathological effects may also decrease after menopause, for example, in severe forms of dengue and influenza (Klein et al.,; Guerra-Silveira & Abad-Franch, ).

Sex steroid hormones modulate immunocompetence

The immune system comprises innate and adaptive defense strategies. Innate immunity is the first line of defense and recognizes microbe-specific structures triggering phagocytosis, cell lysis, and secretion of cytokines. The latter stimulates an adaptive cellular immune response, which by means of cytokine secretion and antibody production specifically eradicates pathogens and infected cells.

Already in 1898, a potential link between sex hormones and the immune system has been proposed by Calzoari. He recognized changes in the thymus after castration (Calzoari, ). More observations along these lines were described later on: women have more CD4+ T cells (Amadori et al., ) and higher levels of circulating immunoglobulins (Ig), in particular IgM (Butterworth et al.,; Rhodes et al.,; Grundbacher, ). Also, women suffer more often from autoimmune diseases (Jacobson et al.,; Whitacre et al., ). Sex steroid hormones are thought to contribute to differences in humoral and cellular responses to infection and vaccination in men and women (Cook, ).

Gonadal hormones exert specific effects on the male and female immunocompetence at both the cellular and the molecular level (Fig.1A). Estrogen receptors are expressed in most cells of the innate and adaptive immune system including T cells, B cells, neutrophils, macrophages, dendritic cells (DC), and natural killer (NK) cells (Fish, ). Androgen receptors were identified in T and B lymphocytes. During pregnancy, activated lymphocytes also express progesterone receptors (Bouman et al., ).

Estrogens affect innate immune cells. Estrogens at levels of ovulatory phase or pregnancy suppress cytotoxicity of NK cells (Hao et al., ). Notably, macrophages treated in vitro with estradiol showed decreased secretion of the proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (Kramer et al., ), whereas long-term in vivo administration led to increased secretion of IL-1β, IL-6, and IL-12p40 after Toll-like receptor (TLR) 4 activation and eventually an enhanced activation status (Calippe et al., ). In vitro monocytes produce more IL-1β, IL-12, and TNF-α (Bouman et al.,; Gonzalez et al., ). Estradiol increases the anti-inflammatory and decreases the chemotactic activity of neutrophils (Ashcroft et al., ). Estrogen receptor signaling also regulates lineage development of DCs (Seillet et al., ). High estradiol levels promote the development of conventional IL-12-producing DCs and the expansion of IFN-γ-producing killer DCs. In addition, production of IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by immature DCs is increased (reviewed in Fish, ). In plasmacytoid DCs, the production of type 1 interferons (IFN) is enhanced in response to viral or exogenous nucleic acids via TLR7 and TLR9 (Seillet et al., ), whereas progesterone downregulates TLR9-mediated IFN-α production in response to viral infections potentially increasing a woman's risk for HIV and herpes simplex virus (HSV) (Hughes et al., ). In innate immune cells, testosterone decreases while estradiol increases the expression of TLR4 (Rettew et al.,, ).

Both estrogens and androgens reduce the numbers of immature T lymphocytes enhancing thymic involution during puberty and pregnancy (Tanriverdi et al.,; Olsen & Kovacs, ). Also adaptive immunity differs between men and women (Fig.1A): Androgens stimulate the development of Th1 responses and activate CD8+ T cells, whereas estrogens stimulate Th2 responses and activate antibody production (Giron-Gonzalez et al.,; Fish,; Gonzalez et al., ). In women at reproductive age compared to age-matched men, the CD4+/CD8+ ratio is significantly increased (Seli & Arici, ). Low estrogen levels are paralleled by an increased expression of the transcription factor T-bet (T-box expressed in T cells), which in due course shifts the balance toward Th1 immunity and IFN-γ expression. High estrogen levels inhibit IRF1 (interferon regulatory factor 1) favoring Th2 immunity and IL-4 expression (Fish, ). This distinct shift from Th1 toward Th2 as well as the activity of regulatory T cells is enhanced by high progesterone levels during pregnancy, often leading to autoimmune disease remission yet also an elevated susceptibility toward certain infectious diseases, for example, influenza or malaria (Klein et al.,; Pazos et al., ). Partially controversial results were reported regarding hormonal effects on the cytokine secretion pattern of T lymphocytes (reviewed in Bouman et al.,; Straub,; Gonzalez et al.,; Oertelt-Prigione, ). Interestingly, no effects of sex steroid hormones on IL-4 and IL-10 production could be found so far. Data on the secretion of IFN-γ and IL-2 are conflicting (Bouman et al.,; Straub,; Oertelt-Prigione, ). Naïve CD4+ T cells from women proliferated faster while producing more IFN-γ and less IL-17A compared to male T cells; this sex-specific cytokine imbalance was mediated by androgens (Zhang et al., ). Significantly, more regulatory T cells were found during the menstrual cycle when estrogen levels are high (Arruvito et al., ). Estrogen levels also play a role in T-cell homing, by enhancing the expression of chemokine receptors CCR1 and CCR5 in CD4+ cells (Yung et al.,; Mo et al., ). Testosterone increases IL-10 production, and men with androgen deficiencies have higher levels of IL-1β, IL-2, TNF-α, antibody titers, and CD4+/CD8+ T-cell ratios (Klein et al., ).

Sex steroid hormones also modulate B-cell development and function (Fig.1A, reviewed in Sakiani et al., ). Estrogens and androgens suppress B lymphopoiesis in the bone marrow. Estradiol reduces apoptosis of immature B cells and thus increases the emergence of autoreactive B cells from central and peripheral checkpoints. However, estradiol also increases somatic hypermutation and class-switch recombination leading to high-affinity Ig-producing cells. These effects might contribute to an improved humoral response in women and explain the increased susceptibility to autoimmune diseases. In contrast to estrogens, progesterone suppresses somatic hypermutation and class-switch recombination (Sakiani et al., ). In the presence of androgens, apoptosis of immature B cells was enhanced and efficient class-switch recombination was inhibited, potentially limiting IgM to IgG conversion but also the pathogenicity of autoimmune reactions (Klein et al.,; Sakiani et al., ). Estrogens also exhibit indirect effects on the immune system by modulating the levels of growth hormone, prolactin, or thymosin. Besides that, it is generally accepted that sex steroid hormones influence lifespan and healthy life expectancy also through other pathways (reviewed in Regan & Partridge, ).

Thus, the general paradigm on sex steroid hormones influencing the immune system stipulates that estrogens have immune-enhancing effects. In contrast, progesterone and androgens such as testosterone exert mainly immunosuppressive properties.

Age and sex-specific changes of the immune system

The immune as well as the endocrine system experiences profound changes with aging, thereby increasing the susceptibility to infectious diseases (Gavazzi & Krause, ) and decreasing the efficacy of vaccination (Grubeck-Loebenstein et al., ). Immunosenescence impacts on the function of the innate as well as the adaptive immune system (reviewed in Panda et al.,; Ademokun et al.,; Agrawal & Gupta,; Arnold et al.,; Mahbub et al.,; Weinberger & Grubeck-Loebenstein,; Scholz et al., ). The functional capacity of innate immune cells declines. A diminished phagocytic capacity of DCs also leads to impaired antigen presentation and activation of the adaptive immune system. Involution of the thymus decreases the output of naïve T cells, and antigen-experienced T cells accumulate constricting the T-cell repertoire. Highly differentiated effector T cells produce more pro-inflammatory cytokines, which together with activated innate immune cells contribute to a systemic pro-inflammatory milieu in older age. Thus, developing specific vaccines and adjuvant immunization strategies appears imperative to ensure healthy aging (Boraschi et al., ).

Both men and women at advancing age exhibit reduced abilities to mount appropriate antibody responses especially toward new antigens. So far, sex-specific differences in the aging immune system and the effect of declining estrogen and progesterone levels on immunosenescence are poorly understood. At menopause, estradiol production in the ovaries ceases. Thereafter, only basal levels of progesterone are being synthetized by the adrenal glands. In aged women, dehydroepiandrosterone (DHEA) and testosterone levels decrease, yet follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels rise from the 4th decade onwards (Al-Azzawi & Palacios, ). In men, there is a slower yet steady decline in testosterone levels from their 2nd to 8th decade of life displaying no clear turning point (Bhasin et al., ). In turn, estradiol, estrone, LH, and FSH gradually increase (Morley et al.,; Jasuja et al., ).

The menopause has a distinct impact on the female immune system (Fig.1B). Postmenopausal women exhibit a reduced number of total lymphocytes, mainly B and CD4+ T lymphocytes (Giglio et al., ). Similarly, after surgical menopause, the CD4+/CD8+ ratio and the numbers of circulating B cells are decreasing, while NK cells are increasing (Kumru et al., ). Pronounced endocrine changes alter the expression of inflammatory mediators thereby elevating plasma IL-1β, IL-6, IL-10, and TNF-α with menopause (Deguchi et al.,; Kamada et al.,; Vural et al.,; Yasui et al., ). After a transient rise in postmenopausal women, IFN-γ levels gradually decrease with age. Yet the production of IL-10 increases during the postmenopausal period (Deguchi et al., ).

Functional aspects of age/sex-specific differences of the immune system and its interplay with changing sex steroid hormone levels have not been investigated extensively (Fig.1B). Transcriptomic analysis of peripheral mononuclear blood cells of young and elderly individuals revealed that significantly more pathways were altered in women than men in particular highlighting lower T-cell defense and more inflammation in female seniors (Marttila et al., ). Women of reproductive age were shown to have significantly higher CD4+ T-cell and lower NK-cell counts, and at older ages, postmenopause reference ranges were comparable for both sexes (Jentsch-Ullrich et al., ). Yet another study showed age-related changes in lymphocyte subsets suggesting a faster progression of immunosenescence in men with a more pronounced decline of T cells including naïve CD4+ and CD8+CD28+, B cells, T-cell proliferative capacity, and IL-6 secretion, and a weaker increase in CD4+ memory T cells and NK cells (Hirokawa et al., ). Age-related alterations in T-cell cytokine secretion were also described to be sex specific, as IFN-γ and IL-17 secretion were decreased in elderly men after in vitro stimulation but not in women (Goetzl et al., ). IL-10 secretion was increased in elderly women but not in men (Pietschmann et al., ).

Hormone replacement therapy (HRT) in women showed beneficial effects on the immune system, as menopause-related immunological changes were partly reversed (Fig.1B). Estrogens especially increased B-lymphocyte numbers and decreased pro-inflammatory cytokine production (Kamada et al.,,; Porter et al., ). Baseline elevated IL-6 levels were significantly decreased, also was the production of IL-6 in stimulated PBMCs (Berg et al.,; Saucedo et al., ). Estradiol HRT reversed the postmenopausal increase in NK-cell activity (Albrecht et al., ) and reduced LPS-induced TNF-α production in monocytes (Aune et al., ). HRT also resulted in a significant reduction in plasma TNF-α and IL-1β levels (Vural et al., ) and IL-10 production (Deguchi et al., ). Yet the effect of estradiol on the increased secretion of Type 2 vs. Type 1 cytokines remains controversial (Kumru et al.,; Xia et al., ). Potential effects of testosterone replacement therapy on the immune system have not been addressed systematically. Its beneficial effects in elderly, in particular frail men, remain unclear as well as the risk of adverse events (Spitzer et al., ).

Age-related changes in sex steroid levels enhance immunosenescence-related alterations. In women, this can be partially reversed by HRT.

Vaccine efficacy in men and women: is the sex bias maintained after menopause?

Sex-specific responses to distinct vaccines have been reported, unfortunately however solely in a minority of trials. Vaccination success in women, similar to stronger humoral and cellular responses after infection, is thought to be mediated through the action of sex steroid hormones (Cook, ). Based on 57 studies that actually stratified data according to sex, 54 of these studies reported clear vaccination side effects (Cook, ). Still large comprehensive data sets assessing sex-specific responses to vaccination are scarce, influenza vaccination being the sole exception. Before 1977, the FDA prohibited women in childbearing age to participate in phase 1 and 2 clinical trials, very probably this being still the reason why more or exclusively men are being enrolled. Since 1993, gendered analyses are required; however, reported data are sex-stratified only in rare cases (Simon,; Geller et al., ).

In vaccinated adults, sex-related differences have been observed in immunogenicity and clinical effectiveness for influenza (Wang et al.,; Cook et al.,; Hui et al.,; Couch et al.,; Nichol et al.,; Engler et al.,; Falsey et al.,; Klein et al.,,; Talaat et al.,; Khurana et al.,; Furman et al., ), pneumococcal polysaccharide (Sankilampi et al.,; Wagner et al.,; Brandao et al.,; Cook et al.,; Goldblatt et al.,; Soneji & Metlay,; Wiemken et al., ), hepatitis A and B (reviewed in Cook,; Klein et al., ), tetanus (Marvell & Parish, ), diphtheria (Hasselhorn et al., ), measles (Green et al., ), meningococcal (Edwards et al.,; Krasnicka, ), yellow fever (Monath et al.,; Pfister et al.,; Veit et al., ), rabies (Briggs et al.,; Banga et al., ), smallpox (Kennedy et al., ), Venezuelan equine encephalitis (Pittman et al., ), brucella (Rhodes et al., ), and HSV2 vaccine (Corey et al.,; Stanberry et al., ). Yet distinct documentation on sex-specific responses in probands of advanced age is extremely scarce. Those studies which have disclosed information on, or, specifically tackled coverage, adverse events, immunogenicity, and effectiveness are listed in Table2.

Despite higher morbidity and mortality during influenza pandemics, women actually show a better response to influenza vaccination, in particular by mounting higher levels of neutralizing antibodies (Wang et al.,; Cook et al.,; Nichol et al.,; Engler et al.,; Falsey et al.,; Klein et al.,; Furman et al., ). However, side effects were significantly more frequent in female vaccinees (Cook et al.,; Engler et al.,; Cook,; Klein et al., ) perhaps due to a concomitant high expression of inflammatory cytokines (Furman et al., ). Women being vaccinated with half doses had geometric mean titers comparable to men having received a full dose (Engler et al., ), and men with high testosterone levels mounted lower titers of neutralizing antibody suggesting a immunosuppressive role for testosterone in the context of influenza vaccination (Furman et al., ).

Women are more susceptible to HSV2 (Table1). A recombinant glycoprotein D vaccine yielded a 38–42% efficacy in HSV1 seronegative women, yet was not efficacious at all in men and in HSV1 seropositive women (Stanberry et al., ). Studies in mice showed that estradiol increases the efficacy of HSV2 vaccine (Pennock et al., ). Women also react stronger to hepatitis B vaccination as 5% men after age 29 were nonresponders, whereas women only dropped to this level after age 43, yet exhibiting no actual advantage after menopause (Vermeiren et al., ).

Women are generally immune-privileged. Yet in some exceptions, men are better protected, for example, against diphtheria and tetanus (Table1). This correlates with higher levels of seroprotection (Table2). In this context, military immunizations and higher rates of injury with consecutive immunization in men are considered decisive (Gergen et al.,; Volzke et al., ). Protective antitetanus titers were found in 60% of men aged 70+ with a history of military service compared to 20–30% of not serving men and < 20% in women (Gergen et al., ). Diphtheria vaccination failed twice as often in women and resulted in significantly lower antibody titers (Hasselhorn et al., ). Yet prior to the introduction of common diphtheria vaccination, more boys than girls suffered from diphtheria, which interestingly reversed after puberty (Deacon, ).

In this context, also the type of antigen used for vaccination appears crucial. Naturally acquired immunity primarily provided by antipneumococcus protein-specific antibodies knows no sex difference during ages below 65. Interestingly, in women below 65, the titers of polysaccharide-specific antibodies were significantly higher (P < 0.05). Later in life this difference vanishes, and now, aged men had statistically significantly higher levels against the major surface proteins PspA and CbpA (P < 0.05) (Simell et al., ). Notably, vaccination with a pneumococcal polysaccharide vaccine (PPV23) mounted significantly (up to 30%) higher antibody levels in men of advanced ages (Sankilampi et al.,; Brandao et al.,; Goldblatt et al., ).

DHEA failed as a vaccination adjuvant in human trials (reviewed in Hazeldine et al., ). Despite that, HRT based on estrogens may increase responsiveness in elderly women as vaccination studies performed during different phases of the ovarian cycle in younger individuals showed significantly higher efficacy in line with high estrogen levels. Cholera vaccination during the follicular phase of the menstrual cycle was superior (Kozlowski et al., ). Also data from animal studies support the assumption that HRT may improve vaccine effectiveness. Vaccination of ovariectomized rhesus macaques was characterized by an increased frequency of terminally differentiated CD4+ effector memory T cells and inflammatory cytokine-secreting memory T cells as well as a reduction in T-cell cytokine and IgG production. This could be partly reversed by HRT (Engelmann et al., ). Estradiol also improved the efficacy of a vaccine against genital herpes in mice (Bhavanam et al.,; Pennock et al., ). The combination of estradiol and influenza vaccination induced neutralizing antibody titers in ovariectomized mice comparable to intact mice (Nguyen et al., ).

Conclusion and future perspectives

Specific immune responses differ in aging men and women (Table3). Besides genetic factors, these differences can be explained through the greatly divergent and changing levels of sex steroid hormones and their interplay with the immune system. Estrogens promote while androgens suppress immune responses during infections, after vaccination or in case of autoimmunity. On these grounds, men are more susceptible against many taxa, while female suffer more from diseases with enhanced immunopathological impact. Studies on how aging affects these sex-related differences in immunity are rare. Based on epidemiological data, women appear to lose their immunological advantage after menopause. To what degree hormonal levels are effective in this context needs to be assessed in more detail. Data from animal studies suggest effects of HRT on vaccine efficacy, again requiring more careful evaluations in humans. Women at high estrogen levels commonly mount a stronger humoral response. This effect could however not be generalized for any vaccine type. Therefore, further improvement of vaccination response may be feasible in postmenopausal women as well as aging men. To date, most vaccines have been tested and adjusted in male probands. Hence, efforts in individualizing dosing and vaccination schedules may achieve enhanced protection and reduction of side effects in women. Although current clinical trials are sex-matched, sex-specific evaluations are rarely disclosed despite being highly desirable.

In summary, the gender gap in life and healthy life expectancy stems from gender and sex-related differences. Both have to be addressed to achieve a longer and healthier life in humans: (i) behavioral factors related to rate of infection need to be altered thereby increasing vaccination coverage and booster immunizations, (ii) composition and dosage of vaccines need to be adjusted to comply with sex-specific differences in immunity, and (iii) preclinical data warrant human trials on combining short-term HRT with vaccinations to improve vaccine efficacy.

Search strategy and selection criteria

The data presented in this review were compiled by searches of PubMed, the clinicaltrial.gov registry, Cochrane, FDA, and EMEA databases from November 2013 to September 2014 using the search terms (alone or in combination) ‘menopause’, ‘immunosenescence’, ‘sex or gender’, ‘immune system’, ‘estrogen or estradiol’, ‘testosterone’, ‘androgen’, ‘progesterone’, ‘sex hormone’, ‘women’, ‘hormone replacement therapy’, ‘vaccine or vaccination’, ‘sex difference’, ‘influenza’, ‘pneumococcus’, ‘herpes zoster or varicella’, ‘hepatitis’, ‘herpes simplex’, ‘tetanus’, ‘diphtheria’, ‘pertussis’, ‘encephalitis’, ‘vaccination rate or coverage’, ‘adverse reactions’, ‘seroprevalence or seroprotection’, ‘antibody or humoral’, and ‘efficacy or effectiveness’. Studies that failed to analyze differences by sex were excluded. Only papers published in English or German were used. Also, the primary literature of cited review articles was reevaluated.

Funding

This work was supported by the European Union's Seventh Framework Program MOPACT (‘Mobilizing the potential of active aging in Europe’; FP7-SSH-2012-1 grant agreement no. 320333).

Conflict of interest

None declared.

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    Beyer WE, Palache AM, Kerstens R, Masurel N. Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies. Eur. J. Clin. Microbiol. Infect. Dis. 1996;15:65-70.

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    Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D'Agostino R, Vasan RS. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 2011;96:2430-2439.

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    Brandao AP, de Oliveira TC, de Cunto Brandileone MC, Goncalves JE, Yara TI, Simonsen V. Persistence of antibody response to pneumococcal capsular polysaccharides in vaccinated long term-care residents in Brazil. Vaccine. 2004;23:762-768.

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    Briggs DJ, Dreesen DW, Nicolay U, Chin JE, Davis R, Gordon C, Banzhoff A. Purified Chick Embryo Cell Culture Rabies Vaccine: interchangeability with Human Diploid Cell Culture Rabies Vaccine and comparison of one versus two-dose post-exposure booster regimen for previously immunized persons. Vaccine. 2000;19:1055-1060.

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    Tetanus surveillance—United States, 2001–2008. MMWR. 2011;60:365-369.

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    Chor JSY, Ngai KL, Goggins WB, Wong MCS, Wong SYS, Lee N, Leung T-f, Rainer TH, Griffiths S, Chan PKS. Willingness of Hong Kong Healthcare Workers to Accept Pre-Pandemic Influenza Vaccination at Different WHO Alert Levels: Two Questionnaire Surveys. 2009.

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    Cohn AC, MacNeil JR, Harrison LH, Hatcher C, Theodore J, Schmidt M, Pondo T, Arnold KE, Baumbach J, Bennett N, Craig AS, Farley M, Gershman K, Petit S, Lynfield R, Reingold A, Schaffner W, Shutt KA, Zell ER, Mayer LW, Clark T, Stephens D, Messonnier NE. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease. Clin. Infect. Dis. 2010;50:184-191.

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    Cook IF, Barr I, Hartel G, Pond D, Hampson AW. Reactogenicity and immunogenicity of an inactivated influenza vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine. 2006;24:2395-2402.

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    Cook IF, Pond D, Hartel G. Comparative reactogenicity and immunogenicity of 23 valent pneumococcal vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine. 2007;25:4767-4774.

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    Corbel MJ. 2006.

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    Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Douglas JM, Handsfield HH, Warren T, Marr L, Tyring S, DiCarlo R, Adimora AA, Leone P, Dekker CL, Burke RL, Leong WP, Straus SE. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA. 1999;282:331-340.

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    Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, Sigurdardottir B, Hoeper A, Graham IL, Edelman R, He F, Nino D, Capellan J, Ruben FL. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine. 2007;25:7656-7663.

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    Dentico P, Buongiorno R, Volpe A, Zavoianni A, Pastore G, Schiraldi O. Long-term immunogenicity safety and efficacy of a recombinant hepatitis B vaccine in healthy adults. Eur. J. Epidemiol. 1992;8:650-655.

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    Dittmann S, Wharton M, Vitek C, Ciotti M, Galazka A, Guichard S, Hardy I, Kartoglu U, Koyama S, Kreysler J, Martin B, Mercer D, Rønne T, Roure C, Steinglass R, Strebel P, Sutter R, Trostle M. Successful control of epidemic diphtheria in the States of the Former Union of Soviet Socialist Republics: lessons learned. J. Infect. Dis. 2000;181:S10-S22.

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    Dworkin MS, Park L, Borchardt SM. The changing epidemiology of invasive Haemophilus influenzae Disease, Especially in Persons ⩾65 Years Old. Clin. Infect. Dis. 2007;44:810-816.

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    Edwards KM, Burns VE, Adkins AE, Carroll D, Drayson M, Ring C. Meningococcal A vaccination response is enhanced by acute stress in men. Psychosom. Med. 2008;70:147-151.

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    Engelmann F, Barron A, Urbanski H, Neuringer M, Kohama SG, Park B, Messaoudi I. Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques. Age. 2011;33:275-289.

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    Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, Klimov A, Keitel WA, Nichol KL, Carr WW, Treanor JJ. Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 2008;168:2405-2414.

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    Age-specific sex-related differences in infections: a statistical analysis of national surveillance data in Japan. · 2012
    Not checked
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    Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J. Infect. Dis. 2009;200:172-180.

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    Filia A, Bella A, von Hunolstein C, Pinto A, Alfarone G, Declich S, Rota MC. Tetanus in Italy 2001–2010: a continuing threat in older adults. Vaccine. 2013;32:639-644.

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  59. 59.

    Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 2008;8:737-744.

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    Flanagan KL. Sexual dimorphism in biomedical research: a call to analyse by sex. Trans. R. Soc. Trop. Med. Hyg. 2014;108:385-387.

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    Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, St Louis ME. Herpes simplex virus type 2 in the United States, 1976 to 1994. N. Engl. J. Med. 1997;337:1105-1111.

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    Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, Bernard H, Fruth A, Prager R, Spode A, Wadl M, Zoufaly A, Jordan S, Kemper MJ, Follin P, Muller L, King LA, Rosner B, Buchholz U, Stark K, Krause G. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N. Engl. J. Med. 2011;365:1771-1780.

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    Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiebaut R, Tibshirani RJ, Davis MM. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc. Natl Acad. Sci. USA. 2014;111:869-874.

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    Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM. Male gender is associated with increased risk for postinjury pneumonia. Shock. 2004;21:410-414.

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    Garenne M. Sex differences in measles mortality: a world review. Int. J. Epidemiol. 1994;23:632-642.

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    Gavazzi G, Krause KH. Ageing and infection. Lancet Infect. Dis. 2002;2:659-666.

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    Geller SE, Koch A, Pellettieri B, Carnes M. Inclusion, analysis, and reporting of sex and race/ethnicity in clinical trials: have we made progress? J. Womens Health (2002). 2011;20:315-320.

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    Gergen PJ, McQuillan GM, Kiely M, Ezzati-Rice TM, Sutter RW, Virella G. A population-based serologic survey of immunity to tetanus in the United States. N. Engl. J. Med. 1995;332:761-766.

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    Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L, Indiveri F, Costantini S. Immune cell circulating subsets are affected by gonadal function. Life Sci. 1994;54:1305-1312.

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    Giron-Gonzalez JA, Moral FJ, Elvira J, Garcia-Gil D, Guerrero F, Gavilan I, Escobar L. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. Eur. J. Endocrinol. 2000;143:31-36.

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    Goetzl EJ, Huang MC, Kon J, Patel K, Schwartz JB, Fast K, Ferrucci L, Madara K, Taub DD, Longo DL. Gender specificity of altered human immune cytokine profiles in aging. FASEB J. 2010;24:3580-3589.

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    Goldblatt D, Southern J, Andrews N, Ashton L, Burbidge P, Woodgate S, Pebody R, Miller E. The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years. Clin. Infect. Dis. 2009;49:1318-1325.

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    Goldenberg RL, Andrews WW, Faye-Petersen OM, Goepfert AR, Cliver SP, Hauth JC. The Alabama Preterm Birth Study: intrauterine infection and placental histologic findings in preterm births of males and females less than 32 weeks. Am. J. Obstet. Gynecol. 2006;195:1533-1537.

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    Gonzalez DA, Diaz BB, Rodriguez Perez Mdel C, Hernandez AG, Chico BN, de Leon AC. Sex hormones and autoimmunity. Immunol. Lett. 2010;133:6-13.

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    Govaert TM, Dinant GJ, Aretz K, Masurel N, Sprenger MJ, Knottnerus JA. Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial. BMJ. 1993;307:988-990.

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    Green MS, Shohat T, Lerman Y, Cohen D, Slepon R, Duvdevani P, Varsano N, Dagan R, Mendelson E. Sex differences in the humoral antibody response to live measles vaccine in young adults. Int. J. Epidemiol. 1994;23:1078-1081.

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    Greinacher A, Friesecke S, Abel P, Dressel A, Stracke S, Fiene M, Ernst F, Selleng K, Weissenborn K, Schmidt BMW, Schiffer M, Felix SB, Lerch MM, Kielstein JT, Mayerle J. Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet. 2011;378:1166-1173.

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    Grubeck-Loebenstein B, Berger P, Saurwein-Teissl M, Zisterer K, Wick G. No immunity for the elderly. Nat. Med. 1998;4:870.

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  79. 79.

    Grundbacher FJ. Human X chromosome carries quantitative genes for immunoglobulin M. Science. 1972;176:311-312.

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  80. 80.
    Sex Bias in Infectious Disease Epidemiology: Patterns and Processes · 2013
    No notice
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    Gutierrez F, Masia M, Mirete C, Soldan B, Rodriguez JC, Padilla S, Hernandez I, Royo G, Martin-Hidalgo A. The influence of age and gender on the population-based incidence of community-acquired pneumonia caused by different microbial pathogens. J. Infect. 2006;53:166-174.

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    Hainz U, Jenewein B, Asch E, Pfeiffer KP, Berger P, Grubeck-Loebenstein B. Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. Vaccine. 2005;23:3232-3235.

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  83. 83.

    Hao S, Zhao J, Zhou J, Zhao S, Hu Y, Hou Y. Modulation of 17β-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors. Int. Immunopharmacol. 2007;7:1765-1775.

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  84. 84.

    Hasselhorn HM, Nubling M, Tiller FW, Hofmann F. [Diphtheria booster immunization for adults]. Dtsch. Med. Wochenschr. (1946). 1997;122:281-286.

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  85. 85.

    Hazeldine J, Arlt W, Lord JM. Dehydroepiandrosterone as a regulator of immune cell function. J. Steroid Biochem. Mol. Biol. 2010;120:127-136.

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  86. 86.
    The epidemiology of pertussis in Germany: past and present · 2009
    Not checked
  87. 87.
    Slower immune system aging in women versus men in the Japanese population · 2013
    No notice
  88. 88.

    Höhler T, Groeger-Bicanic G, Hoet B, Stoffel M. Antibody persistence and immune memory elicited by combined hepatitis A and B vaccination in older adults. Vaccine. 2007;25:1503-1508.

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  89. 89.

    Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int. J. Tuberc. Lung Dis. 1998;2:96-104.

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  90. 90.

    Hoschler K, Thompson C, Andrews N, Galiano M, Pebody R, Ellis J, Stanford E, Baguelin M, Miller E, Zambon M. Seroprevalence of influenza A(H1N1)pdm09 virus antibody, England, 2010 and 2011. Emerg. Infect. Dis. 2012;18:1894-1897.

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  91. 91.

    Hughes GC, Thomas S, Li C, Kaja M-K, Clark EA. Cutting edge: progesterone regulates IFN-α production by plasmacytoid dendritic cells. J. Immunol. 2008;180:2029-2033.

    Not in our library10.4049/jimmunol.180.4.2029

  92. 92.

    Hui SL, Chu LW, Peiris JS, Chan KH, Chu D, Tsui W. Immune response to influenza vaccination in community-dwelling Chinese elderly persons. Vaccine. 2006;24:5371-5380.

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    Jackson LA, Austin G, Chen RT, Stout R, DeStefano F, Gorse GJ, Newman FK, Yu O, Weniger BG. Safety and immunogenicity of varying dosages of trivalent inactivated influenza vaccine administered by needle-free jet injectors. Vaccine. 2001;19:4703-4709.

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  94. 94.

    Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 1997;84:223-243.

    Not in our library10.1006/clin.1997.4412

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    Jasuja GK, Travison TG, Davda M, Murabito JM, Basaria S, Zhang A, Kushnir MM, Rockwood AL, Meikle W, Pencina MJ, Coviello A, Rose AJ, D'Agostino R, Vasan RS, Bhasin S. Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. J. Gerontol. A Biol. Sci. Med. Sci. 2013;68:733-740.

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  96. 96.

    Jentsch-Ullrich K, Koenigsmann M, Mohren M, Franke A. Lymphocyte subsets' reference ranges in an age- and gender-balanced population of 100 healthy adults—A monocentric German study. Clin. Immunol. 2005;116:192-197.

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  97. 97.

    Kamada M, Irahara M, Maegawa M, Yasui T, Takeji T, Yamada M, Tezuka M, Kasai Y, Aono T. Effect of hormone replacement therapy on post-menopausal changes of lymphocytes and T cell subsets. J. Endocrinol. Invest. 2000;23:376-382.

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    Kamada M, Irahara M, Maegawa M, Ohmoto Y, Takeji T, Yasui T, Aono T. Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am. J. Obstet. Gynecol. 2001a;184:309-314.

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  99. 99.

    Kamada M, Irahara M, Maegawa M, Yasui T, Yamano S, Yamada M, Tezuka M, Kasai Y, Deguchi K, Ohmoto Y, Aono T. B cell subsets in postmenopausal women and the effect of hormone replacement therapy. Maturitas. 2001b;37:173-179.

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  100. 100.

    Kennedy RB, Ovsyannikova IG, Pankratz VS, Vierkant RA, Jacobson RM, Ryan MA, Poland GA. Gender effects on humoral immune responses to smallpox vaccine. Vaccine. 2009;27:3319-3323.

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  101. 101.

    Khattab MA, Eslam M. The impact of host factors on management of hepatitis C virus. Hepat. Mon. 2012;12:235-241.

    Not in our library10.5812/hepatmon.709

  102. 102.

    Khurana S, Verma N, Talaat KR, Karron RA, Golding H. Immune response following H1N1pdm09 vaccination: differences in antibody repertoire and avidity in young adults and elderly populations stratified by age and gender. J. Infect. Dis. 2012;205:610-620.

    Not in our library10.1093/infdis/jir791

  103. 103.

    Klein SL. Hormonal and immunological mechanisms mediating sex differences in parasite infection. Parasite Immunol. 2004;26:247-264.

    Not in our library10.1111/j.0141-9838.2004.00710.x

  104. 104.

    Klein SL, Pekosz A. Sex-based biology and the rational design of influenza vaccination strategies. J. Infect. Dis. 2014;209:S114-S119.

    Not in our library10.1093/infdis/jiu066

  105. 105.

    Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect. Dis. 2010a;10:338-349.

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    Klein SL, Passaretti C, Anker M, Olukoya P, Pekosz A. The impact of sex, gender and pregnancy on 2009 H1N1 disease. Biol. Sex Differ. 2010b;1:5.

    Not in our library10.1186/2042-6410-1-5

  107. 107.

    Klein SL, Pekosz A, Passaretti C, Anker M, Olukoya P. Sex, Gender and Influenza. 2010c;1-58.

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  108. 108.

    Klein SL, Marks MA, Li W, Glass GE, Fang LQ, Ma JQ, Cao WC. Sex differences in the incidence and case fatality rates from hemorrhagic fever with renal syndrome in China, 2004–2008. Clin. Infect. Dis. 2011;52:1414-1421.

    Not in our library10.1093/cid/cir232

  109. 109.

    Klein SL, Hodgson A, Robinson DP. Mechanisms of sex disparities in influenza pathogenesis. J. Leukoc. Biol. 2012;92:67-73.

    Not in our library10.1189/jlb.0811427

  110. 110.

    Klismanic Z, Juretic KB, Tripkovic I. Epidemiological characteristics of invasive meningococcal disease in the Split-Dalmatia County 1996–2010. Acta Clin. Croat. 2013;52:485-491.

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  111. 111.

    Kozlowski PA, Williams SB, Lynch RM, Flanigan TP, Patterson RR, Cu-Uvin S, Neutra MR. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J. Immunol. 2002;169:566-574.

    Not in our library10.4049/jimmunol.169.1.566

  112. 112.

    Kramer PR, Kramer SF, Guan G. 17 beta-estradiol regulates cytokine release through modulation of CD16 expression in monocytes and monocyte-derived macrophages. Arthritis Rheum. 2004;50:1967-1975.

    Not in our library10.1002/art.20309

  113. 113.

    Krasnicka B. Evaluation of the Immunogenicity, Safety, Reactogenicity, Effectiveness and Lot Consistency of Menveo. 2010;1-42.

    Not in our library

  114. 114.

    Kumru S, Godekmerdan A, Yilmaz B. Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J. Reprod. Immunol. 2004;63:31-38.

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    Kumru S, Yildiz FM, Godekmerdan A, Kutlu S, Yilmaz B, Gurates B. Effects of raloxifene and hormone replacement therapy on serum Th2 and Th3 type cytokine concentrations in healthy postmenopausal women: a randomised controlled trial. Arch. Gynecol. Obstet. 2008;277:489-493.

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    Leimkugel J, Hodgson A, Forgor AA, Pfluger V, Dangy JP, Smith T, Achtman M, Gagneux S, Pluschke G. Clonal waves of Neisseria colonisation and disease in the African meningitis belt: eight- year longitudinal study in northern Ghana. PLoS Med. 2007;4:e101.

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    Hepatitis E in England and Wales · 2008
    Not checked
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    Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 2010;10:594-604.

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    Magdei M, Melnic A, Benes O, Bukova V, Chicu V, Sohotski V, Bass A. Epidemiology and control of diphtheria in the Republic of Moldova, 1946–1996. J. Infect. Dis. 2000;181(Suppl 1):S47-S54.

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    Marvell DM, Parish HJ. Tetanus prophylaxis and circulating antitoxin in men and women. Br. Med. J. 1940;2:891-895.

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    Monath TP, Nichols R, Archambault WT, Moore L, Marchesani R, Tian J, Shope RE, Thomas N, Schrader R, Furby D, Bedford P. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. Am. J. Trop. Med. Hyg. 2002;66:533-541.

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    Morley JE, Kaiser FE, Perry Iii HM, Patrick P, Morley PMK, Stauber PM, Vellas B, Baumgartner RN, Garry PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46:410-413.

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    Morris CA, Oliver PR, Reynolds F, Selkon JB. Intradermal hepatitis B immunization with yeast-derived vaccine: serological response by sex and age. Epidemiol. Infect. 1989;103:387-394.

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    Sexual Inequality in Tuberculosis · 2009
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    Nguyen DC, Masseoud F, Lu X, Scinicariello F, Sambhara S, Attanasio R. 17beta-Estradiol restores antibody responses to an influenza vaccine in a postmenopausal mouse model. Vaccine. 2011;29:2515-2518.

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    Nhamoyebonde S, Leslie A. Biological differences between the sexes and susceptibility to tuberculosis. J. Infect. Dis. 2014;209:S100-S106.

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    Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N. Engl. J. Med. 2007;357:1373-1381.

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    Oksuzyan A, Juel K, Vaupel JW, Christensen K. Men: good health and high mortality. Sex differences in health and aging. Aging Clin. Exp. Res. 2008;20:91-102.

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    Olsen NJ, Kovacs WJ. Evidence that androgens modulate human thymic T cell output. J. Investig. Med. 2011;59:32-35.

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    Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol. 2009;30:325-333.

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    Pazos M, Sperling RS, Moran TM, Kraus TA. The influence of pregnancy on systemic immunity. Immunol. Res. 2012;54:254-261.

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    Pennock JW, Stegall R, Bell B, Vargas G, Motamedi M, Milligan G, Bourne N. Estradiol improves genital herpes vaccine efficacy in mice. Vaccine. 2009;27:5830-5836.

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    Pfister M, Kursteiner O, Hilfiker H, Favre D, Durrer P, Ennaji A, L'Age-Stehr J, Kaufhold A, Herzog C. Immunogenicity and safety of BERNA-YF compared with two other 17D yellow fever vaccines in a phase 3 clinical trial. Am. J. Trop. Med. Hyg. 2005;72:339-346.

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    Pichichero ME, Rennels MB, Edwards KM, Blatter MM, Marshall GS, Bologa M, Wang E, Mills E. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA. 2005;293:3003-3011.

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    Pittman PR, Makuch RS, Mangiafico JA, Cannon TL, Gibbs PH, Peters CJ. Long-term duration of detectable neutralizing antibodies after administration of live-attenuated VEE vaccine and following booster vaccination with inactivated VEE vaccine. Vaccine. 1996;14:337-343.

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    Poethko-Müller C, Schmitz R. Vaccination coverage in German adults: results of the German Health Interview and Examination Survey for Adults (DEGS1). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013;56:845-857.

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    Porter VR, Greendale GA, Schocken M, Zhu X, Effros RB. Immune effects of hormone replacement therapy in post-menopausal women. Exp. Gerontol. 2001;36:311-326.

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    Quandelacy TM, Viboud C, Charu V, Lipsitch M, Goldstein E. Age- and sex-related risk factors for influenza-associated mortality in the United States between 1997–2007. Am. J. Epidemiol. 2014;179:156-167.

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    Quinn TC, Overbaugh J. HIV/AIDS in women: an expanding epidemic. Science. 2005;308:1582-1583.

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    Rakasz E, Lynch RG. Female sex hormones as regulatory factors in the vaginal immune compartment. Int. Rev. Immunol. 2002;21:497-513.

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    Regan JC, Partridge L. Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. Best Pract. Res. Clin. Endocrinol. Metab. 2013;27:467-479.

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    Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol. Reprod. 2008;78:432-437.

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    Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology. 2009;150:3877-3884.

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    Reutter J, Bart PA, Francioli P, Safary A, Frei PC. Production of antibody to hepatitis A virus and hepatitis B surface antigen measured after combined hepatitis A/hepatitis B vaccination in 242 adult volunteers. J. Viral Hepatitis. 1998;5:205-211.

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    Rhodes K, Scott A, Markham RL, Monk-Jones ME. Immunological sex differences. A study of patients with rheumatoid arthritis, their relatives, and controls. Ann. Rheum. Dis. 1969;28:104-120.

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    Roberts CW, Walker W, Alexander J. Sex-associated hormones and immunity to protozoan parasites. Clin. Microbiol. Rev. 2001;14:476-488.

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    Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter ML, Danila R, Cieslak P, Shutt KA, Popovic T, Schuchat A, Harrison LH, Reingold AL. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J. Infect. Dis. 1999;180:1894-1901.

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    Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat. Rev. Endocrinol. 2013;9:56-62.

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    Sandman L, Davidson M, Krugman S. Inactivated hepatitis A vaccine: a safety and immunogenicity study in health professionals. J. Infect. Dis. 1995;171(Suppl 1):S50-S52.

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    Sankilampi U, Honkanen PO, Bloigu A, Herva E, Leinonen M. Antibody response to pneumococcal capsular polysaccharide vaccine in the elderly. J. Infect. Dis. 1996;173:387-393.

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    Saucedo R, Rico G, Basurto L, Ochoa R, Zarate A. Transdermal estradiol in menopausal women depresses interleukin-6 without affecting other markers of immune response. Gynecol. Obstet. Invest. 2002;53:114-117.

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    Scholz JL, Diaz A, Riley RL, Cancro MP, Frasca D. A comparative review of aging and B cell function in mice and humans. Curr. Opin. Immunol. 2013;25:504-510.

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  166. 166.
    Low Acceptability of A/H1N1 Pandemic Vaccination in French Adult Population: Did Public Health Policy Fuel Public Dissonance? · 2010
    No notice
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    Scott JA, Hall AJ, Dagan R, Dixon JM, Eykyn SJ, Fenoll A, Hortal M, Jette LP, Jorgensen JH, Lamothe F, Latorre C, Macfarlane JT, Shlaes DM, Smart LE, Taunay A. Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7,000 episodes of invasive disease. Clin. Infect. Dis. 1996;22:973-981.

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    Seillet C, Rouquie N, Foulon E, Douin-Echinard V, Krust A, Chambon P, Arnal JF, Guery JC, Laffont S. Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha. J. Immunol. 2013;190:5459-5470.

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    Serfung RE, Sherman IL, Houseworth WJ. Excess pneumonia-influenza mortality by age and sex in three major influenza A2 epidemics, United States, 1957–58, 1960 and 1963. Am. J. Epidemiol. 1967;86:433-441.

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    Simell B, Lahdenkari M, Reunanen A, Kayhty H, Vakevainen M. Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins. Clin. Vaccine Immunol. 2008;15:1391-1397.

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    Simon V. Wanted: women in clinical trials. Science. 2005;308:1517.

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    Sleeman K, Knox K, George R, Miller E, Waight P, Griffiths D, Efstratiou A, Broughton K, Mayon-White RT, Moxon ER, Crook DW. Invasive pneumococcal disease in England and Wales: vaccination implications. J. Infect. Dis. 2001;183:239-246.

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    Sočan M, Frelih T, Janet E, Petraš T, Peternelj B. Reactions after pneumococcal vaccine alone or in combination with influenza vaccine. Vaccine. 2004;22:3087-3091.

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    Soneji S, Metlay J. Mortality reductions for older adults differ by race/ethnicity and gender since the introduction of adult and pediatric pneumococcal vaccines. Public Health Rep. 2011;126:259-269.

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    Song M, Tang Q, Rayner S, Tao XY, Li H, Guo ZY, Shen XX, Jiao WT, Fang W, Wang J, Liang GD. Human rabies surveillance and control in China, 2005–2012. BMC Infect. Dis. 2014;14:212.

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    Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat. Rev. Endocrinol. 2013;9:414-424.

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    Spolarics Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock. 2007;27:597-604.

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    Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G. Glycoprotein-D–adjuvant vaccine to prevent genital herpes. N. Engl. J. Med. 2002;347:1652-1661.

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    Stark K, Schonfeld C, Barg J, Molz B, Vornwald A, Bienzle U. Seroprevalence and determinants of diphtheria, tetanus and poliomyelitis antibodies among adults in Berlin, Germany. Vaccine. 1999;17:844-850.

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    Talaat KR, Greenberg ME, Lai MH, Hartel GF, Wichems CH, Rockman S, Jeanfreau RJ, Ghosh MR, Kabongo ML, Gittleson C, Karron RA. A single dose of unadjuvanted novel 2009 H1N1 vaccine is immunogenic and well tolerated in young and elderly adults. J. Infect. Dis. 2010;202:1327-1337.

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    Tanaka E, Sata M, Nakano H, Suzuki H, Tanikawa K. Antibody response to inactivated hepatitis A vaccine. Hepatol. Res. 1997;9:103-112.

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    Thomas SL, Hall AJ. What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect. Dis. 2004;4:26-33.

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  188. 188.
    Gender differences in healthy life years within the EU: an exploration of the “health–survival” paradox · 2012
    No notice
  189. 189.

    Veit O, Niedrig M, Chapuis-Taillard C, Cavassini M, Mossdorf E, Schmid P, Bae H-G, Litzba N, Staub T, Hatz C, Furrer H. Immunogenicity and safety of yellow fever vaccination for 102 HIV-infected patients. Clin. Infect. Dis. 2009;48:659-666.

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    Vermeiren AP, Hoebe CJ, Dukers-Muijrers NH. High non-responsiveness of males and the elderly to standard hepatitis B vaccination among a large cohort of healthy employees. J. Clin. Virol. 2013;58:262-264.

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    Villa E, Karampatou A, Camma C, Di Leo A, Luongo M, Ferrari A, Petta S, Losi L, Taliani G, Trande P, Lei B, Graziosi A, Bernabucci V, Critelli R, Pazienza P, Rendina M, Antonelli A, Francavilla A. Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology. 2011;140:818-829.

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    Vina J, Borras C, Gambini J, Sastre J, Pallardo FV. Why females live longer than males: control of longevity by sex hormones. Sci. Ageing Knowl. Environ. 2005;2005:pe17.

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    Vitek CR, Brisgalov SP, Bragina VY, Zhilyakov AM, Bisgard KM, Brennan M, Kravtsova ON, Lushniak BD, Lyerla R, Markina SS, Strebel PM. Epidemiology of epidemic diphtheria in three regions, Russia, 1994–1996. Eur. J. Epidemiol. 1999;15:75-83.

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    Volzke H, Kloker KM, Kramer A, Guertler L, Doren M, Baumeister SE, Hoffmann W, John U. Susceptibility to diphtheria in adults: prevalence and relationship to gender and social variables. Clin. Microbiol. Infect. 2006;12:961-967.

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    Vural P, Akgul C, Canbaz M. Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol. Res. 2006;54:298-302.

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    Wagner C, Popp W, Posch M, Vlasich C, Rosenberger-Spitzy A. Impact of pneumococcal vaccination on morbidity and mortality of geriatric patients: a case-controlled study. Gerontology. 2003;49:246-250.

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    Wagner KS, White JM, Lucenko I, Mercer D, Crowcroft NS, Neal S, Efstratiou A. Diphtheria in the postepidemic period, Europe, 2000–2009. Emerg. Infect. Dis. 2012;18:217-225.

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    Wang C-S, Wang S-T, Chou P. Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community. Vaccine. 2002;20:2494-2499.

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    Webster M, Libranda-Ramirez BD, Aligui GD, Olveda RM, Ouma JH, Kariuki HC, Kimani G, Olds GR, Fulford AJ, Butterworth AE, Dunne DW. The influence of sex and age on antibody isotype responses to Schistosoma mansoni and Schistosoma japonicum in human populations in Kenya and the Philippines. Parasitology. 1997;114(Pt 4):383-393.

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    Weinberger B, Grubeck-Loebenstein B. Vaccines for the elderly. Clin. Microbiol. Infect. 2012;18(Suppl 5):100-108.

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    Recall responses to tetanus and diphtheria vaccination are frequently insufficient in elderly persons. · 2013
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    Whitacre CC, Reingold SC, O'Looney PA. A gender gap in autoimmunity. Science. 1999;283:1277-1278.

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    White WG, Barnes GM, Barker E, Gall D, Knight P, Griffith AH, Morris-Owen RM, Smith JW. Reactions to tetanus toxoid. J. Hyg. 1973;71:283-297.

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    HIV and Gender. 2003;1-4.

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    Adressing Sex and Gender in Epidemic-Prone Infectious Diseases. 2007;1-40.

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    Wiemken TL, Carrico RM, Klein SL, Jonsson CB, Peyrani P, Kelley RR, Aliberti S, Blasi F, Fernandez-Gonzalez R, Lopardo G, Ramirez JA. The effectiveness of the polysaccharide pneumococcal vaccine for the prevention of hospitalizations due to Streptococcus pneumoniae community-acquired pneumonia in the elderly differs between the sexes: results from the Community-Acquired Pneumonia Organization (CAPO) international cohort study. Vaccine. 2014;32:2198-2203.

    Not in our library10.1016/j.vaccine.2014.02.048

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    Wolters B, Junge U, Dziuba S, Roggendorf M. Immunogenicity of combined hepatitis A and B vaccine in elderly persons. Vaccine. 2003;21:3623-3628.

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    Xia X, Zhang S, Yu Y, Zhao N, Liu R, Liu K, Chen X. Effects of estrogen replacement therapy on estrogen receptor expression and immunoregulatory cytokine secretion in surgically induced menopausal women. J. Reprod. Immunol. 2009;81:89-96.

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    Yasui T, Maegawa M, Tomita J, Miyatani Y, Yamada M, Uemura H, Matsuzaki T, Kuwahara A, Kamada M, Tsuchiya N, Yuzurihara M, Takeda S, Irahara M. Changes in serum cytokine concentrations during the menopausal transition. Maturitas. 2007;56:396-403.

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    Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology. 2013;81:928-930.

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    Yung R, Williams R, Johnson K, Phillips C, Stoolman L, Chang S, Richardson B. Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice. Arthritis Rheum. 1997;40:1334-1343.

    Not in our library10.1002/1529-0131(199707)40:7<1334::aid-art19>3.0.co;2-8

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    Zhang MA, Rego D, Moshkova M, Kebir H, Chruscinski A, Nguyen H, Akkermann R, Stanczyk FZ, Prat A, Steinman L, Dunn SE. Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way. Proc. Natl Acad. Sci. USA. 2012;109:9505-9510.

    Not in our library10.1073/pnas.1118458109

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    Zhu F-C, Huang S-J, Wu T, Zhang X-F, Wang Z-Z, Ai X, Yan Q, Yang C-L, Cai J-P, Jiang H-M, Wang Y-J, Ng M-H, Zhang J, Xia N-S. Epidemiology of zoonotic hepatitis E: a community-based surveillance study in a rural population in China. PLoS ONE. 2014;9:e87154.

    Not in our library10.1371/journal.pone.0087154

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    Zhuang H, Cao XY, Liu CB, Wang GM. Epidemiology of hepatitis E in China. Gastroenterol. Jpn. 1991;26(Suppl 3):135-138.

    Not in our library10.1007/bf02779283

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