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Sex Differences in the Immune Response to Vaccines

By Roberta Attanasio

Women and men respond differently to infectious microbes and vaccines – it is said, indeed, that the immune system of women is stronger than the immune system of men. Stronger or weaker, one thing is certain – men and women are not the same in terms of immune response. A few years ago, the journal Lancet Infectious Diseases published “ The Xs and Y of immune responses to viral vaccines” – a comprehensive article that clearly shows how the biological differences between sexes influence the immune response to vaccines, as for example the influenza, yellow fever and hepatitis vaccines. There are not many published studies on the same subject, though. The majority of scientists involved in vaccine research do not consider sex as a variable and, typically, vaccine trials are not designed to take into account the physiological differences that exist between men and women.


If we had to take these differences into account, how would things change when vaccinating human populations? In the New York Times article “Do women need such big flu shots?” Op-Ed contributors Sabra Klein and Phyllis Greenberger provide an example related to one of the influenza vaccines: “Under the current guidelines, men and women are to get equal-sized doses of the H1N1 vaccine. Yet women’s bodies generate a stronger antibody response than men’s do, research shows, so less vaccine may be needed to immunize them. If we could give women a smaller dose, there would be more vaccine to go around. And we might also spare them the mild side effects that vaccines can cause, like pain at the injection site, inflammation and fever. All of these are more common in women than in men.”

In 2010, the World Health Organization published “Sex, Gender and Influenza”, a report that “focuses on the different effects of seasonal epidemics, pandemics and localized outbreaks of influenza on males and females including pregnant women.” The report concludes that “significantly more research is required to gain a more complete understanding of the complex and varied effects of sex and gender on influenza infection and vaccination, and underscores the need to consider their interplay with any infectious disease of global concern.”

However, there are still large gaps in our understanding of how sex differences influence the immune response to vaccines and not enough research is done to fill these gaps. May be, step by step, we’ll get there. Meanwhile, here is one of the steps – a new study found that high levels of testosterone make the immune response to the flu vaccine go south.

The study – “Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination” – was carried out using samples from 53 women and 34 men vaccinated with a seasonal influenza vaccine. Results from the study not only show that women displayed significantly stronger antibody responses to the vaccine – they also show that men with the highest levels of testosterone displayed the lowest antibody responses to the vaccine. Thus, testosterone has immunosuppressive activity.

The authors of the study speculate that lower antibody responses in men might provide an evolutionary advantage. Women produce higher levels of antibodies, but also develop stronger inflammatory responses which, in many instances, lead to more severe disease. Males of many species are more likely to experience trauma than females – thus, their risk of contracting infections because of open wounds is higher. By keeping their responses at a low gear configuration, men can control potentially dangerous inflammation.


  • ankovalli

    In my immunology of infectious disease class we learned that the majority of the harm that our bodies go through doing infection is not due to the pathogen, but can be attributed to the reaction of our immune system. Inflammation is generally the immune response that is attributed to destruction of healthy cells surrounding the site of infection. That being said, inflammation is absolutely necessary to fight off infections when they do occur. This is especially true for women because some pathogens can cross the placental barrier. To prevent this from happening, women need to have a strong inflammatory response and robust antibody production to destroy the pathogens before they can affect the fetus. It is very interesting how men and women have biological differences that enhance their mutualistic relationship.

  • Christine

    It is not surprising to read that there are sex differences in the immune response of vaccine for males and females. As a matter of fact, I am currently working in a Neuroscience lab where one of the studies that are being done is looking at sex differences in the brain of male and females rats and how they differ from each other. So in reading this I found it interesting because I wonder if production of estrogen and testosterone also makes a difference not only in immune response but also in other things such as behavior or diseases.
    One thing I also found interesting when reading this article is how women not only produce higher levels of antibodies, but also develop stronger inflammatory responses, this made me wonder doesn’t that mean women more likely to develop immune disorder such as a cytokine storm during an influenza infection. Since it seems estrogen is connected to inflammation, I would think this would cause more proliferation and differentiation of lymphocytes and monocytes, which are involved in inflammation thus increasing the more likelihood of a cytokine storm happening. I would also think that this would put women more at a higher risk for developing an autoimmune disease. In learning all this I find it very intriguing because this explains why I read recently on the NIH website, how women are more likely to develop Rheumatoid arthritis than men, an autoimmune disease that leads to inflammation in the joints and tissues.
    In knowing this now, I agree with giving women a smaller dose of vaccine than men, maybe more time should be spent in developing a vaccine for women that aids in controlling inflammation which as stated lead to them developing more severe diseases.

  • xyZee

    The way nature works, survival of the species trumps survival of the individual. So the traits that are more favorable for the survival of the species will be prevalent in a population even if the trait is not favorable for the survival of an individual. This is the paradox I came across in my parasitology class; sickle cell anemia is a serious condition that can lead to death, but in certain areas of Africa that are endemic for malaria it is prevalent. The Plasmodium spp. require red blood cells for their life cycle, but cannot reproduce inside the red blood cells of those that have sickle cell anemia due to the altered shape of the red blood cells. A similar paradox occurs here as well. A man who has high levels of testosterone might get infected, and due to the immunosupressant properties of testosterone, might succumb to the infection and die. But it is favorable for the survival of the species for men to have high levels of testosterone.

  • dpitts5

    I think scientist should consider sex, gender and all other factors when developing vaccines. Knowing that women produce a greater antibody response than men there is no reason for men and women to receive equal dosages. I believe it would make more sense for women to receive a lower dosage. A dosage low enough to where their antibody response is equal to the males antibody response, that way it’s still able to fight infection. The production of less vaccine can be a financial advantage for the country as a whole. The money we save on less vaccine production could go toward more research on why exactly testosterone is immunosupressive to the flu vaccine, or understanding the effects when it comes to sex and gender in relation to the flu and its vaccine. With a better understanding of each of these issues there is a possibility that men will be able to have an increased antibody response to the flu vaccine.

  • JHernandez

    Many cells of the immune system including dendritic cells, macrophages, natural killer cells, and lymphocytes express estrogen receptors on their surfaces (1,2). Scientists have found that higher estrogen levels increases B cell activation, professional antigen presentation, and secretion of cytokines (2). These receptors have been associated with the stronger immune response seen in females to infections and vaccines. However, this increased activity seen of the immune system is also believed to be the reason why patients with autoimmune diseases are more likely to be females. Studies continue to be conducted to elucidate the mechanisms through which estrogen influences an immune response, particularly as autoimmune diseases gain more limelight in the public eye. From an economic sense and as a preventative measure against pressures that lead to autoimmunity, lower vaccine doses should be administered to females if they continue to provide protection without eliciting a larger immune response than necessary.

    Cunningham, M., & Gilkeson, G. (2011). Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol, 40(1), 66-73. doi: 10.1007/s12016-010-8203-5
    Verthelyi, D. (2006). Female’s heightened immune status: estrogen, T cells, and inducible nitric oxide synthase in the balance. Endocrinology, 147(2), 659-661. doi: 10.1210/en.2005-1469

  • Nhan

    If it’s common knowledge that men and women are not the same in regards to their immune response, why are scientists not taking these physiological differences into consideration when developing vaccines? I find it odd that these developers are essentially ignoring an important factor that may change how effective certain vaccines can be. If we look at the difference in doses recommended for children and adults, we find that the reason being is obvious. Immune responses for various age groups are different. This brings me back to the question, if age is considered a variable in vaccine trails, why not sex? Studies have shown that women generate a stronger antibody response than men, and if scientists use this information to give women a smaller dosage, a lot of the side effects involved in vaccination would lessen. It seems to me that for immunization in women, less is more. Economically, this can be beneficial because if less is being administered to women, then more can be given to others who need it. This will probably mean males in their prime can get higher doses to compensate for their low antibody responses. If that happens, would more males experience complications like inflammation and fever? Surely, the immune system would respond differently since men are used to receiving a certain dosage, but would it be for the worse? The only way to know is through trials. I hope that in the future, sex differences will play a bigger role when designing vaccines for the public.

    • Z. Haqqani

      Well, immune response and its correlation to sex wasn’t really common knowledge before, and it probably still isn’t since we’re reading an article about it just now, in 2014. Some years before, it was more of a thing that was observed by some, but maybe passed off as trivial. The first paragraph of the article adds that there are not many published studies done on this subject, and if it’s not published it’s usually not accepted or applied. It is only now being brought to people’s attention as beneficial knowledge. I do believe that in the near future they may start to give different doses of vaccine to females than they do males, however, I do not think they’d prescribe a higher dose for older males, since they already tend to have more negative responses to vaccines than younger males do.

    • mashim331

      Although women have stronger response to vaccine than men, the effectiveness of the vaccine is still the same regarding both sexes. I think this is the reason why people have been ignoring to differentiate vaccines based on sex. The fact that women experience more pain at the injection site, inflammation or fever may be seen as women’s complaints since they are considered the “weaker” sex. Even among females, the response to the vaccine can also varies, so if we want to separate vaccines for men and women then we also need to consider vaccines for each individual female as well. I guess since we cannot tailor the vaccine for each person, we choose to give a stronger dose for everyone. Females might experience a little bit more pain, yet the vaccine is working.

    • Quasi

      Any medication or vaccination is created utilizing a male as the ideal. They don’t “average it out”. The difference in presentation of immune response (in any individual specimen of person, not just binary male/female) is because of the actual immune response, not the volume of inactive virus injected into a person. Assuming, of course, we’re not filling someone so full of foreign matter they go into shock.

  • Sarah

    Recently, I had read the article about postmenopausal mouse and their response to the influenza vaccine. The article reported that there is a postive correlation between the level of estrogen and the level of antibodies. The result from the article indicates that female mice with normal level estrogen were adept to produce an antibody response to the flu vaccine than female mice that had an ovariectomy. This also concludes that females are more adept than males, due to the fact that females produce more estrogen than males. The study above observing the immunosuppressive role of testostorone to flu vaccine also has a correlation, but the observed perspective is the opposite of estrogen. It’s interesting that humans with low level of testosterone, also have a low lipid metabolism. In an evolutionary stand-point, human females are usually the one carrying the child and protection is important to keep the child alive. As the carrier, high lipid level helps with insulation and protection. The level of antibodies helps ward off pathogens quicker in order to prevent the infection traveling towards the baby. Human males are usually the one out to fight and hunt. Men with low lipid metabolism will probably be less efficient in hunting and fighting. Their energy is needed for “man-power’ during emergencies and it seems that our hormones level were adapting to this situation through evolution. I believe that level of certain hormones pertains to their respective gender, making our immune response gender-dependent.

  • Jonathan Rosenthal

    There were two aspects of this article that caught my eye. The first was the idea that men and women, although similar in many ways, have immune systems that react at different levels of potency. The second aspect of this article that astonished me was the link between testosterone and immunity. This article is claiming that women develop a more potent, and faster reacting, immune defense than do men. This is possibly caused by the presence of testosterone in the host. My question is why does this hormone affect the level of immunity? Can testosterone act as an inhibitor to the cells and molecules of the innate immune system, or does it prevent the recruitment of B and T Lymphocytes?

  • Tylah Hankerson

    Vaccines affecting men and women differently makes sense to me. Males and females produce different hormones that affect each sex differently, like the article said. Diseases also affect men and women differently. It is interesting to me that women are better at producing antibodies than men. I wonder what exactly causes women to produce more antibodies than men. I know the article states that a male with high levels of testosterone produce fewer antibodies but what is it exactly that causes this. Recently for my Immunology to Infectious Disease class, I had to read an article on a postmenopausal mouse response to a flu vaccine. The article basically stated that the flu vaccine wasn’t as effective in postmenopausal females as it is with the general population. This article along with the one posted on here leads me to believe that estrogen production directly helps with antibody production and testosterone directly decreased the production. The article above also states that a low antibody response is an evolutionary advantage. I can see where this can be an advantage and a disadvantage. It is advantage for the reasons stated above in the article. Using what I know from evolutionary biology and the information in this article, those men who produce less testosterone are weaker and therefore selected against while the males who produce more are more successful. I also feel like producing more testosterone could be a disadvantage because one would have a weaker immune response to diseases. Even though having a better antibody immune response could produce a stronger inflammatory response which could be harmful, it could also be beneficial in fighting infections. I hope scientists continue to do more research on female and male antibody production and flu vaccinations because if there is a chance that my flu shots are less painful, then I will be extremely happy.

  • mashim331

    Not too long ago, I read a paper on how estrogen can enhance the performance of B and T cells in post-menopausal female rats in response to influenza vaccine. Basically, more antibodies are made when post-menopausal females are supplied with additional estrogen. By saying that testosterone inhibits the production of antibodies, this article just adds some more reasons to believe in the correlation between sex hormones and immune response to vaccine. Although estrogen and testosterone are present in both sexes, women produce more estrogen and men produce more testosterone. So this makes perfect sense why men have a milder response to vaccine compared to women. However, more testosterone in men is converted into estrogen by an enzyme called aromatase as they age [1]. If the paper on the estrogen is true, this suggests older men can actually produce more antibodies than younger men. So does that make older men more susceptible to vaccine? How strong is the response compared to women? And does the increase in antibodies level due to estrogen rise in older men compensate the aging immune system they have?

    [1] http://www.medicalnewstoday.com/articles/266017.php

    • ankovalli

      Antibody generation normally requires T cell help. T cells develop in the thymus, and because the thymus shrinks as one ages (it is replaced with fat), the amount of naive T cells in circulation is less for older people. This does not discredit the hypothesis that older men may produce a more robust antibody response to secondary infections, but this would mean that younger men are more likely to produce more antibodies against primary infections and vaccines.

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