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It's been one full year into the pandemic and it's clear: women are bearing the brunt of it. And it's not only because women have been forced out of the workplace at disproportionate rates -- hitting the lowest level of female participation in the workplace since 1988 -- or because more than 75% of those working in the healthcare sector are women.
In fact, women appear hardwired to experience COVID-19 and the vaccines differently. Data from the CDC suggests side effects from the vaccines are worse in women; for example, 63 of the total 66 reported cases of anaphylaxis happened in women.
Sabra Klein, PhD, a professor at the Johns Hopkins Bloomberg School of Public Health and co-director of the Center for Women's Health, Sex, and Gender Research, joins us on this week's episode to explain the biological reasons behind the data.
The following is a transcript of her interview with "Track the Vax" host Serena Marshall:
Marshall: Women and COVID. It's a big question. And one, I feel that we maybe don't have a whole lot of answers to. But let's start out with what we do know. I guess mostly, we know women have been disproportionately affected by the pandemic, forced out of the workforce, childcare, less access to health services. But what about the disease itself? Do women and men react to COVID differently?
Klein: So the simple answer is yes, women and men react -- and by react, I'm going to say our immune responses. How our immune system sees the virus and responds to the virus, absolutely differs. I think all too often, the differences between men and women have gone ignored. Not because women are not studied. We are. But all too often, data is not separated for men and women to then analyze data separately to see if we really are responding differently.
And while, as you said, we are being disproportionately affected by this pandemic in terms of childcare, occupation, job loss; and these are losses that are going to take, you know, some estimates, put it at about a decade to get us back to where we were prior to entering into this pandemic.
In terms of our biology and who is suffering worse outcomes? It is generally speaking across very diverse countries, cultures, and societies. It's men in that acute disease that are suffering worse outcomes. When we look at who is being admitted into the intensive care units with severe disease, it is still men. Men are about three times more likely to be admitted into the ICU than are women.
Marshall: That's really a fascinating statistic because you don't really think about a virus impacting a man and a woman differently.
Klein: Thank you. And I think it's that we haven't been able to get this information out to the public in a meaningful way. Because to be honest with you, we have known for decades now that the immune systems of men and women differ and that by and large men are often more susceptible to severe outcomes from viral infections.
We saw this for others what we call beta Coronaviruses, like the SARS-CoV-2 virus that's causing the pandemic right now. We saw this during the SARS epidemic in 2003. We also have seen this during the MERS epidemic, that's still ongoing in the Middle East. So, you know, even for things like hepatitis viruses, we've seen these types of male biases and outcomes.
Marshall: Not trying to make light of the difference in the impact there. But when we talk about man-cold. That's a real thing then? They are actually handling the virus of perhaps a cold differently than a woman does?
Klein: Absolutely, they can. And part of that is the immune response, generally speaking, is typically more robust in women as compared with men. You know, and that's true, both when our immune system sees a virus, so a virus that enters in, in this case, through our respiratory tract. Or, to be frank, when we see a vaccine antigen. So hopefully as many of us are starting to get scheduled or are in line to get scheduled to receive these emergency use authorized vaccines that are available that women tend to respond with a more robust immune response. We see this again in response to lots of vaccines.
Marshall: So I definitely want to come back to the vaccines, but before we get there, let's talk a little bit more about why women have a more robust immune system. Does that have to do with the two X chromosomes with the hormones that women have more of, you know, estrogen, progesterone, or is it something else?
Klein: I love it. Yes, is the answer. The simple answer is yes to both. It turns out that the X chromosome is enriched for immune response genes -- genes that really play fundamental roles in mediating the immune response. They're on the X chromosome. And under most conditions, what textbooks tell us, is that this shouldn't matter because we have a genetic process in place of random X inactivation. Which just means that if you have two X chromosomes, you shouldn't express genes on the X chromosome anymore than another individual who only has one X chromosome, because one copy should be randomly inactivated. Meaning one copy that you receive from either your mother or your father. So that's the maternal or paternal inherited genes.
So you can have this random X-inactivation making, and I love this word, making females a mosaic of X-linked genes. You know, we get that genetic diversity from both the maternal X chromosome, as well as the paternal X chromosome. But it turns out that in humans, about 15% of our X-linked genes, escape X-inactivation. And, and we don't know all the reasons why; but there's some epigenetic mechanisms at play. And what can happen, my group has shown this, others have shown this as well, that certain immune response genes seem to non-randomly escape X-inactivation.
Marshall: So we have extra protection in a way. That's what that means?
Klein: Yes, yes. That's exactly what that means.
Marshall: So women really are the stronger sex.
Klein: Yes. You know, maybe some of it has evolutionary origins for mammals supporting growth of a developing fetus, protecting that developing fetus. We can transfer some, not all, but some of that immunity to the fetus during pregnancy. But you know, the other point that you made about our hormones I think is equally important.
We do know that -- you brought up estrogen and progesterone, both of which are found in higher circulation in women as compared with men. Especially during our reproductive years. So in women prior to menopause. Just about every single immune cell in our bodies have receptors for these hormones. And what that just means for your audience is these hormones can actually regulate the functioning of our immune cells. They can turn on responses, they can turn off responses.
Marshall: Those hormones?
Klein: Those hormones. And it's not just true for estrogen and progesterone, as you mentioned. It's also true for androgens, like testosterone in men. You know, and again, it can be about turning on responses, but it can also be about turning off or dampening those responses. And testosterone is, I would describe it as anti-inflammatory. It turns off a lot of those initial antiviral, inflammatory types of immune responses that really trigger and let your body know that something foreign is there and you need to mount a really protective response.
Marshall: Dr. Klein, just to make sure I'm following here, not only do women have the two X chromosomes that allow extra activation to protect against immune function and response, they have the hormones that turn on response to target the bad guy and men have the hormone that turns off the ability to target the bad guy or the virus?
Klein: That's it exactly. And in this case, the bad guy is the virus. It's not all easy sailing for women. You know, those very responses that are getting turned on and that helped protect us against a virus. They can become dangerous when we turn and mount those responses against ourselves. So, you know, and that's when we develop autoimmune diseases. So that's when, you know, like for systemic lupus erythematosus. Nine-to-one women to men. That's when you start attacking your own DNA. Multiple sclerosis, you're attacking the lining of your nerve fibers. Six-to-one women to men. Turns out that 80% of all autoimmune disease patients are women. And while it is very unusual for the immune system to turn and begin mounting a response against you and your tissues and your cells. When it does happen, it's more likely to be women.
Marshall: Does that play into long COVID? The immune response targeting yourself? Does that have a change in how long COVID is, perhaps, responded to by women versus men?
Klein: I love your hypothesis today. We don't know the answer to that, but we do know that across diverse countries, reports including here in the United States, are indicating that significantly more women are suffering from long COVID than are men. So again, while men may be suffering more during that acute phase in the hospital. Following that initial infection, those long term symptoms -- and these include the most common fatigue, headache; but they can also include that cognitive fog. Feelings of, you know, over-activation of nerves and pain associated with nerve activation. It is women and there are a number of groups, including at Johns Hopkins, who are looking to see if autoantibodies and development of those kinds of immune responses to yourself are contributing to those long-term symptoms.
So your hypothesis has a lot of value. To date, we just don't have the data to know that that is what's mediating why women are more likely to experience the long-term symptoms.
Marshall: Now we've heard anecdotal reports, Dr. Klein, that women with COVID-19 have reported changes to their menstrual cycles. Especially when it comes to that long haul. That if they have a continued fever or they have COVID with a long fever, when they're on their periods, those symptoms actually went away. Do we know why? Or is that just anecdotal and there's no real research behind it?
Klein: Today, we don't know why. But please know that we utilize these anecdotal observations to formulate hypotheses that we can then test in clinical research settings. The same parts of the brain that are associated with induction of fever are also the same parts of our brain that control the hormonal regulation of things like our menstrual cycle.
So, it is absolutely feasible that we would see these types of connections. And we've seen these types of connections between menstruation and other types of even inflammatory diseases. So the connection between your immune system and reproductive function is well known. How it's being affected in COVID, and in particular, in long term COVID we don't yet know.
Marshall: Is that the same for long-term effects? Like, perhaps, fertility and pain, stillbirth, things of that nature?
Klein: Absolutely. Absolutely. And there are a number of investigators looking into this. So I don't think we yet have a clear understanding of whether COVID is leading to fertility problems in the ways in which we saw with Zika, just as an example for comparison.
And we do have evidence that for a subset of women, we are seeing detrimental effects of COVID-19 infection on pregnancy outcomes. Not fertility problems, but pregnancy complications. So today, I don't know that we have any evidence that getting COVID before you attempt or to get pregnant has any impact on your fertility. No evidence of that.
Marshall: Now you didn't just mention vaccines. And I want to talk about, specifically the vaccines, COVID and women. So when it comes to these vaccines that are being distributed now, are women suffering more adverse events from the vaccinations or less because of those, you know, double X-chromosomes and estrogen and progesterone we talked about?
Klein: It's such a good question. So the data that have been coming out thus far show that 77% of the people reporting any adverse events -- so that can be injection site pain, fatigue, headache, fever -- they're women. So women are experiencing, or at least reporting experiencing more adverse events than males.
Marshall: That seems a little counterintuitive, if women aren't suffering that acute onset with COVID as much as males.
Klein: I think we have to think about two things. So first of all, many of these kinds of adverse events are mediated by inflammation. So if women have more of these inflammatory responses that are necessary for protecting you against infection, that could biologically underlie development of these types of adverse reactions.
And I think often counterintuitive for the public is that when you go and get a vaccine, and if you have some pain or you don't feel well, or you have a headache or you develop a mild fever. I can't tell you how many people have told me, anecdotally, they got the flu from receiving the flu vaccine, which is not possible. But what is possible is that you really don't feel well. And it's your immune system at work, giving you that repertoire of symptoms of not feeling well.
Marshall: Giving you the antibodies.
Klein: Yeah, that tells you your immune system is at work and it's generating those responses. And in the process of doing that, that is what makes you not feel well. I think all too often, we think that when we don't feel well -- when we know we have a cold or we have the flu or any number of seasonal infections -- that not feeling well is often being mediated by the immune response that's being mounted to protect you. Not by the presence of that virus in your system.
Marshall: When it comes to that 77% who are reporting more adverse reactions. Do we know that's just because perhaps women report more? They're more likely to go onto the website, file a complaint, then maybe a man would be?
Klein: Absolutely. And so you bring up the second point. That there can be this social or what we in the field like to refer to a gender component. A non-biological explanation for why we would see these types of numbers. So yes, it turns out that women do often report pain and feelings of pain more often than their male counterparts.
Women are often more proactive about their health. They tend to utilize healthcare and healthcare services more than men. So just as you said, getting onto a website and reporting just maybe higher in women as compared with men and you are absolutely correct.
And, you know, I think in the end, we're going to find that it's the intersection of both the social and cultural norms contributing to why women are more likely to report. Mixed with sometimes when we really don't feel well, we are more likely to report because we think this is important. I think there's going to end up being kind of an intersection between that biology and those social and cultural norms.
Marshall: Are the vaccines made for women?
Klein: That is such a good question. Yes, in that -- in 1993 we had the passing of what was referred to as the Revitalization Act and what the Revitalization Act did is it required inclusion of women in clinical trials and all clinical trials.
Marshall: 1993! So, clinical trials before that didn't have to have any women?
Klein: Clinical trials before that did not have to have any women. And more often did not have women. Because in 1977 it was determined that women of reproductive ages should be excluded from clinical trials. That was put in place in an effort to protect pregnant women and their developing fetuses from any potential toxicological effects of drugs or in the case of vaccines, biologics. But what inadvertently happened was we were completely excluded from clinical trials and we were not given autonomy to make a decision for ourselves, to claim that we wanted or didn't want to be included, that we were or were not pregnant, to be included.
And so what was perceived as a safety measure resulted in our complete exclusion until 1993. And now we are included. Okay, and Government Accounting Office audit in 2016 of all NIH, they actually uncovered that now more women than men enroll in clinical trials. So that's really exciting. We are represented, but what's not happening -- and this came out of that accounting report -- is there is no what we call dis-aggregation or separation of the outcome data from men and women and comparison of those data.
So we often don't have publication of data from clinical trials telling us whether a drug or whether a treatment or whether a vaccine or an intervention worked equally well in men and women. Or whether there were differences in reporting of adverse events. Usually that comes out only after a drug or a vaccine or an intervention has gone to market. And it's through reporting that we learn about these differences.
Marshall: Earlier Dr. Klein, you had mentioned that women weren't given the choice to participate in clinical trials. To say whether or not they were pregnant. That does seem to have repeated itself a little bit when it comes to these COVID vaccines. They weren't really given the choice to participate. And instead of subjecting a smaller group of perhaps, possibly pregnant women to the vaccines by their own choice. Now, women are going to get the vaccine who are pregnant and do face a higher risk of COVID and severe outcomes from COVID while pregnant to getting a vaccine they don't really know how it works in pregnancy.
Klein: Everything you say is correct. And you know, there are many societies, organizations associated with ob/gyn who are working tirelessly to correct that. And so those trials are now ongoing. But your points are still heard. When these vaccines were being tested in phase II and phase III clinical trials, pregnancy was an exclusion factor.
So I think going back to this autonomy. We've often not been allowed to be autonomous in making a decision as to whether we do or don't want to be included in a trial. But then we give women almost too much autonomy in deciding what is the correct answer and what will be safe and protective for a pregnant woman and her fetus about receipt of a vaccine for which there really is not ample data upon which to base a decision.
Marshall: Such a fascinating conversation. That sounds like so much of the research is really still out there when it comes to how women will respond to these vaccines differently?
Klein: You are absolutely correct. I think advocacy can be such a strong way to make change. Change in how we do our research. It was advocacy that resulted in Congress changing inclusion of women in 1993.
And I think it's going to be advocacy again ensuring that our, meaning women's responses to vaccines. Whether we are pregnant or not pregnant, whether we are of reproductive ages, or quite frankly, are in our post-menopausal period. That there is a greater need to understand a woman's immune response across the life course. And recognize that this is influencing more than just our reproductive biology and behavior. I think, understanding or appreciating that women's health extends beyond our reproduction is what we really need so that our responses, and in this case, to the vaccine, are really compared to our male counterparts.