By Katie L. Flanagan
Despite the huge body of evidence that males and females have very different immune systems and responses, few biomedical studies consider sex in their analyses. Sex refers to the intrinsic characteristics that distinguish males from females, whereas gender refers to the socially determined behaviour, roles, or activities that males and females adopt. Male and female immune systems are not the same leading to clear sexual dimorphism in response to infections and vaccination.
In 2010, Nature featured a series of articles aimed at raising awareness of the inherent sex bias in modern day biomedical research and, yet, little has changed since that time. They suggested journals and funders should insist on studies being conducted in both sexes, or that authors should state the sex of animals used in their studies, but, unfortunately, this was not widely adopted.
Even before birth, intrauterine differences begin to differentially shape male and female immune systems. The male intrauterine environment is more inflammatory than that of females, male fetuses produce more androgens and have higher IgE levels, all of which lead to sexual dimorphism before birth. Furthermore, male fetuses have been shown to undergo more epigenetic changes than females with decreased methylation of many immune response genes, probably due to physiological differences.
The X chromosome contains numerous immune response genes, while the Y chromosome encodes for a number of inflammatory pathway genes that can only be expressed in males. Females have two X chromosomes, one of which is inactivated, usually leading to expression of the wild type gene. X inactivation is incomplete or variable, which is thought to contribute to greater inflammatory responses among females. The immunological X and Y chromosome effects will begin to manifest in the womb leading to the sex differences in immunity from birth, which continue throughout life.
MicroRNAs (miRNAs) regulate physiological processes, including cell growth, differentiation, metabolism and apoptosis. Males and females differ in their miRNA expression, even in embryonic stem cells, which is likely to contribute to sex differences in the prevalence, pathogenesis and outcome of infections and vaccination.
Females are born with higher oestriol concentrations than males, while males have more testosterone. Shortly after birth, male infants undergo a ‘mini-puberty’, characterised by a testosterone surge, which peaks at about 3 months of age, while the female effect is variable. Once puberty begins, the ovarian hormones such as oestrogen dominate in females, while testicular-derived androgens dominate in males. Many immune cells express sex hormone receptors, allowing the sex hormones to influence immunity. Very broadly, oestrogens are Th2 biasing and pro-inflammatory, whereas testosterone is Th1 skewing and immunosuppressive. Thus, sex steroids undoubtedly play a major role in sexual dimorphism in immunity throughout life.
Sex differences have been described for almost every commercially available vaccine in use. Females have higher antibody responses to certain vaccines, such as measles, hepatitis B, influenza and tetanus vaccines, while males have better antibody responses to yellow fever, pneumococcal polysaccharide, and meningococcal A and C vaccines. However, the data are conflicting with some studies showing sex effects, whereas other studies show none. Post-vaccination clinical attack rates also vary by sex with females suffering less influenza and males experiencing less pneumococcal disease after vaccination. Females suffer more adverse events to certain vaccines, such as oral polio vaccine and influenza vaccine, while males have more adverse events to other vaccines, such as yellow fever vaccine, suggesting the sex effect varies according to the vaccine given. The existing data hint at higher vaccine-related adverse events in infant males progressing to a female preponderance from adolescence, suggesting a hormonal effect, but this has not been confirmed.
If male and female immune systems behave in opposing directions then clearly analysing them together may well cause effects and responses to be cancelled out. Separate analysis by sex would detect effects that were not seen in the combined analysis. Furthermore, a dominant effect in one of the sexes might be wrongly attributed to both sexes. For drug and vaccine trials this could have serious implications.
Given the huge body of evidence that males and females are so different, why do most scientific studies fail to analyse by sex? Traditionally in science the sexes have been regarded as being equal and the main concern has been to recruit the same number of males and females into studies. Adult females are often not enrolled into drug and vaccine trials because of the potential interference of hormones of the menstrual cycle or risk of pregnancy; thus, most data come from trials conducted in males only. Similarly, the majority of animal studies are conducted in males, although many animal studies fail to disclose the sex of the animals used. Analysing data by sex adds the major disadvantage that sample sizes would need to double in order to have sufficient power to detect significant sex effects. This potentially means double the cost and double the time to conduct the study, in a time when research funding is limited and hard to obtain. Furthermore, since the funders don’t request analysis by sex, and the journals do not ask for it, it is not a major priority in today’s highly competitive research environment.
It is likely that we are missing important scientific information by not investigating more comprehensively how males and females differ in immunological and clinical trials. We are entering an era in which there is increasing discussion regarding personalised medicine. Therefore, it is quite reasonable to imagine that females and males might benefit differently from certain interventions such as vaccines, immunotherapies and drugs. The mindset of the scientific community needs to shift. I appeal to readers to take heed and start to turn the tide in the direction whereby analysis by sex becomes the norm for all immunological and clinical studies. The knowledge gained would be of huge scientific and clinical importance.
Dr Katie Flanagan leads the Infectious Diseases Service at Launceston General Hospital in Tasmania, and is an Adjunct Senior Lecturer in the Department of Immunology at Monash University in Melbourne. She obtained a degree in Physiological Sciences from Oxford University in 1988, and her MBBS from the University of London in 1992. She is a UK and Australia accredited Infectious Diseases Physician. She did a PhD in malaria immunology based at Oxford University (1997 – 2000). She was previously Head of Infant Immunology Research at the MRC Laboratories in The Gambia from 2005-11 where she conducted multiple vaccine trials in neonates and infants.
Dr Katie Flanagan’s editorial, ‘Sexual dimorphism in biomedical research: a call to analyse by sex’, is published in the July issue of Transactions of the Royal Society of Tropical Medicine and Hygiene. Transactions of the Royal Society of Tropical Medicine and Hygiene publishes authoritative and impactful original, peer-reviewed articles and reviews on all aspects of tropical medicine.
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By Janet R. Gilsdorf
Every April, when the robins sing and the trees erupt in leaves, I think of Brad — of the curtain wafting through his open window, of the sounds of his iron lung from within, of the heartache of his family. Brad and I grew up at a time when worried mothers barred their children from swimming pools, the circus, and the Fourth of July parade for fear of paralysis. It was constantly on everyone’s minds, cast a shadow over all summertime activities. In spite of the caution, Brad got polio — bad polio, which further terrorized our mothers. It still haunts me. If, somehow, he had managed to avoid the virus for a couple years until the Salk vaccine arrived, none of that — the iron lung, the shriveled limbs, the sling to hold up his head — would have happened.
In 1954, many children in my town, myself included, became “Polio Pioneers” because our parents made us participate in the massive clinical trial of the Salk vaccine. Some of us received the shot of killed virus, others received a placebo. We were proud, albeit scared, to get those jabs, to be part of a big, important experiment. Our moms and dads would have done anything to rid the country of that dreaded disease.
Because the vaccine is so effective, mothers today aren’t terrified of polio. Children in our neighborhoods aren’t growing up in iron lungs or shuffling to school in leg braces. We seem so safe. But our world is smaller than it used to be. The oceans along our coasts can’t stop a pestilence from reaching us from abroad. A polio virus infecting a child in Pakistan, Nigeria, or Afghanistan can hop a plane to New York or Los Angeles or Frankfurt or London, find an unimmunized child, and spread to other unimmunized people. Our earth is not yet free of polio.
Germs are like things that go bump in the night. They can’t been seen, they lurk in familiar places, they are sometimes very harmful, and they instill great fear—some justified, some not.
Fear of measles, like fear of polio, is justified. In the old days, one in twenty children with measles developed pneumonia, one or two in a thousand died. The vaccine changed all that in the developed world. But, measles continues to rage in underdeveloped countries. In a race for very high contagiousness, the measles virus ties the chickenpox virus (which causes another vaccine-preventable childhood infection). Both viruses can catch a breeze and fly. Or they may linger in still air for over an hour. They, too, ride airplanes. This year alone, outbreaks of measles started by imported cases have occurred in New York, California, Massachusetts, Washington, Texas, British Columbia, Italy, Germany, and Netherlands.
Fear of whooping cough (aka pertussis) is also justified. In the pediatric hospital where I work, two young children have died of this infection in the past several years and many others have suffered from the disease, which used to be called “the one-hundred day cough.” It lasts a long time and antibiotic treatment does nothing to shorten the course. Young children with pertussis may quit breathing, have seizures, or bleed into their eyes. It spreads like invisible smoke around high schools and places where people gather … and cough on each other.
On the other hand, fear of vaccines — immunizations against measles, polio, chickenpox, or whooping cough — is hard to understand. In the grand scheme of things, any of these serious infections is a much greater threat than the minimal side effects of a vaccine to prevent them. Just ask the mothers of the children who died of pertussis in my hospital. It’s true that the absolute risk of these infections in resource rich areas is small. But, for even rare infections, a 0.01% risk of disease translates into hundreds of healthy children who don’t have to be sick, or worse yet die, of a preventable infection.
In spite of the great success of vaccines, they aren’t perfect. Perfection is a tall order. Still we can do better. Fortunately, because of the work of my medical and scientific colleagues, new vaccines under development hold promise to be more effective with fewer doses, to provide increased durability of vaccine-induced immunity, and to be even freer of their already rare side effects. And, we’re creating vaccines against respiratory syncytial virus, Staphylococcus aureus, group A Streptococcus, herpes virus, and HIV, to name a few.
Brad would be proud of how far we have come in protecting our children from the horrible affliction that crippled him. He’d also be furious at our failure to vaccinate all our children. Every single one of them. He’d tell us that no child should ever be sacrificed to the ravages of polio or measles or chicken pox or whooping cough.
Janet R. Gilsdorf, MD is the Robert P. Kelch Research Professor of Pediatrics at the University of Michigan Medical School and pediatric infectious diseases physician at C. S. Mott Children’s Hospital, Ann Arbor. She is also professor of epidemiology at the University of Michigan and President-elect of the Pediatric Infectious Diseases Society. Her research focuses on developing new vaccines against Haemophilus influenzae, a bacterium that causes ear infections in children and bronchitis in older adults. She is the author of Inside/Outside: A Physician’s Journey with Breast Cancer and the novel Ten Days.
To raise awareness of World Immunization Week, the editors of Clinical Infectious Diseases, The Journal of Infectious Diseases, Open Forum Infectious Diseases, and Journal of the Pediatric Infectious Diseases Society have highlighted recent, topical articles, which have been made freely available throughout the observance week in a World Immunization Week Virtual Issue. Oxford University Press publishes The Journal of Infectious Diseases, Clinical Infectious Diseases, and Open Forum Infectious Diseases on behalf of the HIV Medicine Association and the Infectious Diseases Society of America (IDSA), and Journal of the Pediatric Infectious Diseases Society on behalf of the Pediatric Infectious Diseases Society (PIDS).
The Journal of the Pediatric Infectious Diseases Society (JPIDS), the official journal of the Pediatric Infectious Diseases Society, is dedicated to perinatal, childhood, and adolescent infectious diseases. The journal is a high-quality source of original research articles, clinical trial reports, guidelines, and topical reviews, with particular attention to the interests and needs of the global pediatric infectious diseases communities.
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Growing up in a pet-less house, except for the occasional goldfish, I always wondered what it would be like to have a pet, especially an exotic one. As a child, my top three picks consisted of the following: an orangutan, a dolphin, and a tiger. A little boy named Jack also has a pet wish list of his own in the book What Pet to Get? by Emma Dodd.
Excited that his mom agreed that he may have a pet, Jack explores his endless pet possibilities. Jack suggests that potentially an elephant, polar bear, or even a T-Rex may work. His mom simply replies that an elephant “might squash the car,” the polar bear may not like the central heating, and the T-Rex wouldn’t be an option because it “has been extinct for sixty-five million years.” What pet did both mom and Jack agree on? Well, let’s just say that Jack’s “little” pet named Fang has a fold out page all to his self. This fun and humorous story with bright, larger-than-life illustrations is a book that young children will enjoy.
Ever wonder what’s going on at home while you’re sunning yourself at the beach? Would you believe that your house is having an adventure of its own? Hey, who says you get to have all the fun?
When the Peterson family leaves for their vacation, their house decides that this might be a good time for it to get away from it all. There is a bit of discussion about this. Trying to get all the parts of a house to agree on a vacation destination is like getting all the members of a family to agree on where to go. But eventually, they come to a consensus and take off. All except the basement, who refuses to rise to the occasion.
The adventure ensues from there, full of puns and silly scenes with a house among oblivious vacationers. Kids will love the silliness, especially if they are old enough to get the plays on words. House Takes a Vacation by Jacqueline Davies is sure to be a hit at storytimes.
Fly Guy fans will not be disappointed when they read the newest book of the Fly Guy series, There Was an Old Lady Who Swallowed Fly Guy. The early chapter book begins with Buzz and his pet, Fly Guy, on their way to visit Grandma—the old lady. When Grandma sees Buzz arrive on his bike she runs to greet her grandson with open arms…and mouth. Before Buzz gets a chance to introduce his amazing pet, Fly Guy is accidentally swallowed by Grandma in their embrace. In the attempt to save Fly Guy, Grandma swallows a spider, a bird, a cat…and so on. Being overwhelmed by all of the animals in Grandma’s stomach, Fly Guy shouts, “Buzz!” After hearing Buzz call back to him, Fly Guy flies his way out of Grandma’s stomach followed by the spider, bird, cat, dog, goat, and cow.
Tedd Arnold’s take on this classic tale is humorous and delightful. Early chapter readers will enjoy the expressive illustrations and clean text as they cheer on Fly Guy to safety. In 2006, Hi! Fly Guy, the first title of this series, received the Theodor Seuss Geisel Honor Award for literary and artistic creativity in a beginning reader book.
Who knew a book comprised of just four simple words could be so much fun? Try saying it aloud: this title has a lyrical, song-like quality. British author Emily Gravett is one of our favorite authors of late, and her newest title does not disappoint. In Orange Pear Apple Bear, pastel watercolors illustrate variations on the word groupings. Gravett says the inspiration for this book came from reading Lynne Truss’s Eats, Shoots and Leaves, which promotes proper grammar. I recently shared this book with a group of preschoolers, who delighted in “reading” along with me by using the pictures as clues.
Gravett’s forthcoming picture book, Monkey and Me, is scheduled for US release in March 2008.
View other titles by Emily Gravett: Wolves and Meerkat Mail
