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Are the SARS-CoV-2 Vaccines Safe for Pregnant and Lactating People?

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by Gertrud U. Rey

Vaccination is the gold standard for preventing infectious diseases and reducing the impact of emerging pathogens. As more and more people are becoming immunized against SARS-CoV-2, a prominent question continues to arise: are the vaccines safe for pregnant and breast-feeding people?

(Image credit: Shutterstock)

None of the clinical trials for SARS-CoV-2 vaccines included pregnant or lactating subjects. Pregnant people in particular are a historically difficult group to study in the context of drug safety because of concerns of liability over potential adverse effects of a new product on a fetus. This lack of safety data further complicates treatment of SARS-CoV-2 infection in pregnant people, who already have an increased risk for premature birth and miscarriage if they become infected. Based on these risk factors, the currently available data, and interim recommendations by the Advisory Committee on Immunization Practices for people over the age of 16, the American College of Obstetricians and Gynecologists recommends that pregnant and lactating people should have access to SARS-CoV-2 vaccines. Fortunately, many pregnant and lactating people have opted to be vaccinated, and the data on the safety and efficacy of vaccination in these two cohorts are beginning to emerge.

A recent publication in the American Journal of Obstetrics and Gynecology describes the safety and immunogenicity of SARS-CoV-2 vaccines in pregnant and lactating women compared to non-pregnant controls and women who had been naturally infected with SARS-CoV-2 during pregnancy. The researchers collected blood and breast milk from 131 women of reproductive age, including 84 pregnant, 31 lactating, and 16 non-pregnant participants who had received two doses of either the Pfizer/BioNTech or Moderna mRNA COVID-19 vaccine; and analyzed the samples for the presence of IgG and IgA antibodies. IgG antibodies are mostly present in the blood and provide the majority of antibody-based immunity against invading pathogens. IgA antibodies are predominantly found in mucus membranes and the fluids secreted by these membranes, including saliva, tears, and breast milk. IgA antibodies are particularly suitable for protecting against pathogens like SARS-CoV-2, which invade the body through these membranes.

Samples were collected at the time of the first and second vaccination, 2 to 6 weeks after the second dose, and at delivery. The researchers also collected umbilical cord blood from 10 infants born during the study period.

The main findings were as follows. Side effects resulting from vaccination were rare and occurred with similar frequency in all participants. These findings are consistent with post-vaccination data tracked by the CDC via the V-safe application, suggesting that post-vaccination reactions in pregnant people are not significantly different from those in non-pregnant people.

Pregnant, lactating, and non-pregnant vaccine recipients produced significantly higher levels of SARS-CoV-2-specific IgG than pregnant women who had been naturally infected. Interestingly, the second vaccine dose led to increased concentrations of coronavirus-specific IgG but not IgA, in both maternal blood and breast milk. The authors speculate that this lack of IgA boosting may have to do with the intramuscular route of immunization, which usually does not induce very high levels of serum IgA. The role of IgA in the serum is mostly secondary to IgG, in that IgA mediates elimination of pathogens that have breached the mucosal surface. In contrast, natural infection induces higher levels of mucosal (IgA) antibodies because SARS-CoV-2 enters the body through the mucosal surfaces. Nevertheless, studies have shown that IgG in breast milk is critical for protecting newborns from other pathogens like HIV, RSV, and influenza. It is possible that this type of antibody is equally important for protecting infants from SARS-CoV-2.

It was previously unclear whether vaccine-induced SARS-CoV-2 antibodies are transferred across the placenta to the fetus. However, the authors also found vaccine-induced IgG in cord blood, suggesting that these antibodies do cross the placenta, as has been previously observed after vaccination of pregnant people against influenza virus, Bordetella pertussis, and other pathogens. Whether these antibodies protect the baby from SARS-CoV-2 infection after birth, remains to be determined.

This study provides the first set of clinical data suggesting that vaccination of pregnant and lactating people against SARS-CoV-2 is both safe and beneficial. Some people have expressed concern over the possible incidence of fever following the second vaccine dose in pregnant people; however, the potential risk to the fetus from a 24-hour fever must be weighed against the possibility of chronic, severe COVID-19 in the mother. Accumulating data suggest that the benefits of vaccination during pregnancy and lactation outweigh the risks of adverse effects to the fetus or infant and align with the abundance of clinical data showing the beneficial effects of vaccinating these groups of people against influenza virus. Analyses of cord blood from infants whose mothers were naturally infected with SARS-CoV-2 during pregnancy indicate that the potential for transfer of antibodies is greater early during gestation, suggesting that immunization during the earlier stages of pregnancy might be preferable. However, more studies are needed to assess the optimal timing of maternal vaccination to achieve enhanced neonatal immunity. In the meantime, these preliminary data allow pregnant and lactating people to make more informed decisions, and also aid physicians in providing evidence-based recommendations.

T cells will save us from COVID-19

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In our quest to stop the COVID-19 pandemic by vaccination, we have been myopically focussed on inducing antibodies against the spike protein. As variants of SARS-CoV-2 have emerged that reduce the ability of such antibodies to block infection, concern has arisen that we will not be able to halt the disease. Such concerns appear to ignore the other important arm of the adaptive immune response: T cells.

Anti-viral antibodies can prevent infection of cells, but when antibody titers are low – years after infection or vaccination – some cells will inevitably be infected. In this case, T cells come to the rescue. Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection.

The T cell response to SARS-CoV-2 infection has been largely ignored for the past year. Certainly, some laboratories have studied T cell responses in patients, and the vaccine makers have dutifully included them along with assays for neutralizing antibodies. But the dialogue has never included T cells as important for resolving disease – but they are for most viral infections. Because T cells can kill virus infected cells, they can help prevent disease and end the infection.

The recent finding that amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity is very good news. In this study, the authors synthesized short peptides covering the entire proteome of multiple SARS-CoV-2 isolates, including the original Wuhan strain, and variants B.1.1.7, B.1.351, P.1, and CAL.20C. They found little difference in the ability of T cells from either convalescent or vaccinated patients to recognize peptides from these viruses. This result means that the amino acid changes in the variants are not likely to impact the ability of T cells to clear infection.

This observation explains why some COVID-19 vaccines have effectively prevented hospitalization and death even in regions where variants circulate widely. In some cases the ability of sera from vaccinated individuals have reduced ability to neutralize infection with some variants. Nevertheless, the vaccines prevent severe COVID-19 and death because T cells can still recognize variant virus-infected cells and clear them.

It’s highly unlikely that vaccination will prevent infection with SARS-CoV-2. Antibody levels rapidly decline after infection or vaccination, especially in the respiratory mucosa. When a virus enters the nasopharynx of an immune individual, it will encounter little antibody opposition and will initiate an infection. However memory B and T cells will spring into action and within a few days produce virus-specific antibodies and T cells. The antibodies will limit infection while the T cells will clear the virus-infected cells. The result is a mild or asymptomatic infection that likely is not transmitted to others.

The recent observations that vaccination appears to prevent asymptomatic infections is a red herring. These studies are being done soon after vaccination when antibody levels in serum and mucosa are high. If these studies were done a year after immunization, the results would be quite different.

Now imagine that you are fully vaccinated and become infected with a SARS-CoV-2 variant. The virus may begin to reproduce rather well in the nasopharynx even in the face of a memory response, because the antibodies are just not good enough to block infection. T cells to the rescue: the T cell epitopes on the surface of the infected cells are readily recognized because they are mainly the same in the variants as in the ancestral strain of SARS-CoV-2. You may have a mild infection but you will not be hospitalized or die. Isn’t that the goal of vaccination?

Why don’t T cell epitopes change as do B cell (antibody) epitopes? A B cell epitope is the same in everyone and so if a virus emerges with a slightly different epitope, it will evade antibody in anyone infected with that virus. T cell epitopes are different. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides.

It is possible that SARS-CoV-2 will continue to produce altered spike proteins that will completely evade antibody neutralization. In this case T cells might not be enough to prevent severe disease – they could be overwhelmed by so many infected cells. Our rush to make vaccines – understandable given the urgency – have led us to such a situation. Most of the vaccines were based only on the spike protein. If we change the spike protein to accommodate variants, we might get in a never-ending cycle of changing COVID-19 vaccines on a regular basis. A better approach would be to produce second-generation COVID vaccines that include other viral proteins besides spike protein. Inactivated and attenuated vaccines fall into this category; another solution would be to modify authorized mRNA vaccines to encode additional viral proteins.

Trial By Error: Clueless Wall Street Journal Op-Ed Endorses PACE as the “Prevailing View” Among Docs

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By David Tuller, DrPH

Long Covid stories and commentaries seem to be everywhere—too many to keep track of! This week, The Wall Street Journal published an opinion piece about long Covid and ME/CFS that is breathtakingly ill-informed—and more importantly, just wrong. Beyond that, it showed remarkable disrespect for patients and their experiences.

(After this low for the WSJ opinion page, what’s next? A piece arguing that women with doctorates should be called “kiddo” rather than “Dr”? Oops!)

The author, Jeremy Devine, is a resident psychiatrist at McMaster University in Ontario, Canada. (In other words, he’s still in training–we all make stupid mistakes when we’re still in training, so perhaps in 20 years Devine will be able to use that excuse when trying to explain away this embarrassment.) Perhaps inexperience explains what might be Devine’s most striking misstep among many: When asserting that psychogenic explanations for ME/CFS represent “the prevailing view among medical practitioners,” he links to the PACE trial.

Is Devine aware of the controversy surrounding PACE? Does he not recognize that it has been effectively discredited, its recommendations dropped years ago by the US Centers for Disease Control and Prevention? Perhaps he did not read the open letter to The Lancet that I organized in 2018 about the PACE trial’s “unacceptable methodological lapses.” The letter was signed by more than 100 experts from Stanford, Columbia, Berkeley, Harvard, University College London, Queen Mary University of London, Johns Hopkins, Georgetown, Yale, etc.

PACE is a likely example of research misconduct, given that the investigators failed to disclose an incredibly salient detail: A significant minority of the sample–13%–met a key outcome threshold at baseline. This study is not something that a McMaster’s resident psychiatrist should be referencing as an example of anything except how not to conduct a clinical trial. (Come to think of it, the open letter to The Lancet has no signatories from McMaster University. Now maybe we know why.)

In fact, the animating trope of Devine’s piece could have been taken directly from the PACE playbook. It amounts to this: People with non-specific complaints who claim to have long Covid are experiencing psychogenic symptoms and/or have a mental illness. That message is delivered without nuance or caveats. (Devine does allow that some might be experiencing genuine physiological symptoms related to a co-morbidity or prior illness.)

Devine doesn’t use the phrase “mass hysteria,” but he might as well have. The thrust of his argument is that long Covid is essentially a crowd-sourced phenomenon—triggered and encouraged by over-the-top social media posts, inflammatory news coverage, and now research funding that will further lead to the “legitimizing” of a non-existent condition and “patient denial of mental illness.” Devine appears to dismiss out-of-hand the possibility that pathophysiological processes could be implicated in these widely reported post-Covid symptoms, including profound exhaustion, cognitive dysfunction, post-exertional malaise, and others. “Long Covid is largely an invention of vocal patient activist groups,” he declares.

Interestingly, Devine considers it a cause for suspicion that patients themselves were the ones who first studied, drew attention to and disseminated information about their own prolonged symptoms. He refers to this as “a highly unorthodox origin” for the category of phenomena we now refer to as long Covid. Yet this was a new pathogen, patients were the ones experiencing said symptoms, and the health care systems in the US and elsewhere were overwhelmed. It is unclear what route of identifying and tracking long Covid would have met Devine’s approval—none, I guess, since he does not believe in the phenomenon in the first place.

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A misogynistic and anti-queer dog whistle

Devine undermines his case by noting that Body Politic, the online community that first surveyed those experiencing post-covid symptoms, “describes itself atop its website’s homepage as ‘a queer feminist wellness collective merging the personal and the political.’” Since Devine presents this Body Politic self-description without further comment, the implication is that an analysis by queers, feminists, and people who see links between their own health and societal inequities is inherently suspect and should not be taken seriously.

Perhaps that kind of appeal to “anti-woke” attitudes resonates with the general readership of the Wall Street Journal opinion page. Certainly the absence of a cogent explanation, or any explanation at all, as to why the sexual orientation and gender politics of those gathering data would automatically bias their findings suggests that Devine is deploying this meme not as a scientific argument but as a misogynistic and anti-queer dog whistle.

Devine makes much of the low numbers of people in the long Covid surveys who received positive viral tests, implying that including them in studies violates core scientific principles. He does not mention a complicating factor: As everyone knows, viral testing was scarce in the first months of the epidemic and patients with suspected or presumed Covid-19 were advised to stay home unless they urgently needed medical care. Devine is essentially presuming that those who are currently suffering but did not obtain a positive viral test are hypochondriacs—and the same goes as well for those who did obtain a positive viral test and are still suffering.

Devine decries the decision by the US Institutes of Health to devote more than $1 billion to studying long Covid as “a victory for pseudoscience.” He suggests that devoting biomedical research resources to long Covid represents “subjugation of scientific rigor to preconceived belief.” It is worth noting that there are few better examples of such “subjugation” than the PACE trial he apparently endorses as the “prevailing view” in the profession.

For what it’s worth, Devine’s opinions are not shared by Anthony Fauci, the nation’s leading infectious disease doctor, who was quoted about long Covid in today’s Los Angeles Times. Here’s the relevant section:

Fauci says it’s impossible to know how many are affected [with long Covid], why the virus doesn’t seem to be done with them or how long their symptoms could last…In the absence of lab tests that can diagnose the problem, “a lot of times people think it’s a psychological disorder,” Fauci said. “It’s not.” (Fauci’s record on ME/CFS stretching back to the 1980s is a different matter that has been documented in Hillary Johnson’s prodigiously reported 1996 book Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic.)

So how does Devine know for sure what he knows for sure about long Covid? He draws—of course!–on parallels between long Covid and what he calls chronic fatigue syndrome. We learn from Devine that ME/CFS patients and others with unexplained symptoms “often vehemently reject a physician’s diagnosis that suggests an underlying mental-health issue, in part because of the stigma around mental illness and the false belief that psychologically generated symptoms aren’t “real.”’

The assertion that patients reject psychological and behavioral interventions because of the stigma around mental illness is a favorite rallying cry of the biopsychosocial ideological brigades. I suppose that could be happening in some cases. But Devine fails to note that patients often reject such a diagnosis because there is insufficient evidence for it beyond the doctor’s opinion–and doctors can be wrong, as we all know. If a doctor keeps insisting based on his/her/their own preconceived ideas about ME/CFS that a patient has a mental illness when they do not, it is not surprising that some respond “vehemently.”

The word “vehemently” is striking. I assume Devine uses it to create the impression that patients are not only irrational but also belligerent and aggressive when they reject wise clinical assessments from doctors like him. Unfortunately, he seems to have some things backwards. He also does not come across as a sympathetic listener. Perhaps Devine will mature with time and, as his psychiatric training progresses, learn to express himself with a greater sense of compassion and a less arrogant approach to patients’ concerns.

And let me say this clearly: Patients should reject the clinical judgment of any physician who reviews the history and conduct of the PACE trial and still endorses it–whether in an opinion piece in The Wall Street Journal, a medical consultation, or anywhere else.

Trial By Error: Another Excellent Read on Long Covid, ME/CFS and Medically Unexplained Symptoms

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By David Tuller, DrPH

In a post earlier this week, I noted some differences in the tenor of the debate over Long Covid in the US and UK. Yesterday, another excellent and in-depth piece on the issues appeared on the domestic front, this time in VICE. The author, Alan Levinovitz, is associate professor of religious studies at James Madison University in Virginia. (School motto, according to Wikipedia: “Knowledge is Liberty.”) Besides religion, Levinovitz writes on a lot of other interesting topics, like science and belief systems and how they intersect. Last year, he published Natural: How Faith in Nature’s Goodness Leads to Harmful Fads, Unjust Laws and Flawed Science. (It’s a good book.)

When the VICE article–“The Medical System Should Have Been Prepared for Long COVID”–popped up on my screen, it had slipped my mind that Levinovitz had contacted me some months ago. I still don’t recall our conversation in great detail, except that he seemed smart and engaged and appeared to be taking ME/CFS and the possible links to Long Covid seriously.

Well, I’m really glad I talked with him. He’s done his research. January’s New York Times Magazine article and other recent pieces explored some of the complicated overlaps between ME/CFS and Long Covid. Now Levinovitz has taken the matter a step further, asking why we don’t know more about post-viral illness in general. His answer, in part, is the long-standing neglect of ME/CFS. This is not news to those involved in the issue. But it is gratifying that a sharp outside observer has weighed the available information and come to the same conclusion.

I sent Levinovitz a message yesterday asking him what drew his interest in covering the issue. Here’s what he wrote:

 I was drawn to the topic because I’ve been interested in the intersection of medicine and belief for a long time, especially psychogenic illness, mass hysteria, placebo and nocebo effects. When I saw what was happening with long Covid it immediately connected to these interests, and I saw a reflexive tendency to classify it as psychogenic.

So then I became curious: Is it psychogenic? And if it were, how would we know? That second question, it turned out, was very hard to answer, in part because the medical community doesn’t have a good way of answering it. Vice was willing to give me the space I needed to unpack these really complicated issues in a way that did them justice.

When I read thoughtful stories like the one in VICE, I don’t expect to agree with everything. I can usually find a point I might have expressed differently or a quote that doesn’t resonate with me, or maybe I would have interviewed those folks instead of these ones. But that’s ok. I’m inside the issue so of course I have strong ideas about how it could be covered. From my perspective, the fact that people not immersed in the field are now curious and are taking the time to poke around and ask questions and write probing articles is itself a sign of enormous change since I began my quixotic project a few years ago.

For his piece, Levinovitz talked to both Jen Brea and Julie Rehmeyer, among others, about the experience of having a poorly understood illness. (Julie, did you refer him to me? I can’t remember now. If so, thanks!) He rightly credits Hillary Johnson’s Osler’s Web, a prodigious feat of reporting, as the “definitive” work about developments in the 1980s and 1990s. He mentions Johnson’s account of Anthony Fauci’s past unwillingness to take ME/CFS seriously—a surprise to many who have only been aware of Fauci as a sane voice amidst the Trump insanity.

What’s more, Levinovitz highlights the PACE trial, the significance of which is often overlooked in US coverage of ME/CFS. I have been trying to discredit PACE since Virology Blog posted my initial investigation more than five years ago, so this lovely passage made my day:

“Despite letters and commentaries (and even scientific studies) the PACE trial remained the gold standard for treatment, endorsed by every major medical organization. Finally, in 2015, the journalist and public health expert David Tuller published a 15,000-word critique of the study, and the tide began to turn.”

(As I have made clear, my work piggy-backed on the devastating critiques of PACE that had already been disseminated by patients and advocates before I wrote anything about it, and the heroic Alem Matthees pursued the tribunal case that liberated the trial data. The discrediting of PACE has been a collective effort.)

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Levinovitz also spoke with bioethicist Diane O’Leary, who has written extensively on so-called “medically unexplained symptoms,” or MUS. The attention to MUS is a welcome development because the term’s problematic implications are little recognized. As I’ve noted previously, the phrase MUS is neutral on its face—as in, “at the present time, these symptoms are medically unexplained.” But champions of the MUS construct often appear to interpret it to mean “medically unexplainable symptoms”—as if the production of all new medical knowledge has ceased. That interpretation has vastly different implications for treatment, research and policy.

(Unlike in the US, the MUS approach is deeply embedded in the UK’s National Health System. . The NHS’ Improving Access to Psychological Therapies program lumps what it refers to as CFS/ME and irritable bowel syndrome, among other conditions, into the MUS category. The IAPT program shunts these patients off to receive CBT and related interventions.)

Levinovitz also communicated with Professor Jon Stone, a neurologist at the University of Edinburgh and an expert in the category called functional neurological disorders, essentially a large subset of MUS. The article included Professor Stone’s thoughts on the thorny issue of “psychogenic non-epileptic seizures.” Yet it did not include a discussion of CODES, the high-profile study of a course of cognitive behavior therapy as a treatment for these seizures–rechristened “dissociative seizures” to reduce the stigma involved with telling people they have a psychogenic disorder. (I have blogged about CODES here, here and here.)

Professor Stone was a CODES co-investigator, as was Professor Trudie Chalder, a cognitive behavior therapy expert at King’s College London and one of the lead investigators of the discredited PACE trial. The main findings were published last year in Lancet Psychiatry, a high-impact journal. With more than 350 participants, CODES was a major test of the biopsychosocial approach to FNDs. The primary outcome of the study was the number of dissociative seizures per month. The CBT was designed specifically to address whatever mechanisms were presumed to be driving these seizures.

Unfortunately for the investigators’ theoretical framework, those who did not receive the specialized seizure-reduction CBT had a greater reduction in seizures at the end of the study than those who did receive the specialized seizure-reduction CBT, although the difference was not statistically significant. In addressing these embarrassing and presumably unexpected results, Chalder, Stone and their colleagues did not conclude that the CBT intervention had failed. Instead, they argued that seizure reduction was likely not the optimal primary outcome after all–even though they had invested significant time and money in the notion that it was. After rejecting the appropriateness of their own primary outcome, they touted some very modest benefits in a few self-reported and subjective secondary outcomes.

King’s College London issued a press release in which Professor Chalder hailed the “effectiveness” of the intervention without mentioning its lack of effectiveness for the primary and most important outcome of seizure reduction. The release itself presented the study as a success but also did not mention the null results for the primary and most important outcome of seizure reduction. Professor Stone was quoted as well in the KCL release; presumably he read it at some point. Perhaps neither he nor Professor Chalder thought it was important for the university to disclose the null results for the primary and most important outcome in disseminating information about the study to the media.

But I digress. Levinovitz ends his VICE piece with a call for doctors to be willing to say “I don’t know.” That call is definitely on point. In a 2020 commentary about MUS in Medical Humanities, a BMJ journal, Northwestern University law professor Steven Lubet and I ended with a similar appeal: “Patients would be better served by greater humility accompanied by an understanding that medical categories are always provisional and therefore subject to change with advances in research.”

Alan Levinovitz has navigated these complex cross-currents with intelligence and empathy and nuance. I am delighted he took this on and gave the matter the attention it deserves.

Five year persistence of Ebolavirus in humans

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Ebolavirus

The current outbreak of Ebolavirus disease in Guinea, which began in February 2021, may have originated from a survivor of the 2013-16 outbreak in the same country.

Phylogenetic analysis of genome sequences revealed that viruses from the current outbreak group with the Makona variant, which caused the 2013-16 epidemic. The new isolates are most closely related to viruses sampled in the same region in August 2014, differing by only 12 and 13 bases. Consequently the recent outbreak in Guinea was not initiated by a spillover from an animal reservoir, as has been the case for all previously studied Ebolavirus outbreaks. Rather the sequence data indicate that the isolates are somehow linked to the 2013-16 outbreak. However, the number of substitutions – 110 – is far less than would be expected had the viruses been transmitted silently from human to human since that time.

The implication of these data is that Ebolavirus remained undetected in a survivor of the 2013-16 outbreak for 5 years. While Ebolavirus is an acute infection – one that is resolved in the host – the extent of the 2013-16 outbreak revealed rare instances of persistence of the virus in survivors. In once case, an individual who had recovered from the disease developed unilateral uveitis 14 weeks after the onset of Ebolavirus disease and 9 weeks after clearance of viremia. Infectious Ebolavirus was isolated from the aqueous humor. Shortly after the declaration of the end of the Ebolavirus outbreak in December 2015, a new cluster of cases was detected in Guinea in February and March 2016. Genome sequence analysis and epidemiological tracing revealed that these cases all originated from a single individual who harbored infectious Ebolavirus in his testes for over 500 days. He passed the infection on to others during sexual intercourse. In this outbreak the viral genomes differed by just 5 mutations from isolates obtained during the previous outbreak.

These observations indicate that Ebolavirus can persist, for at least 5 years, in an infectious form in immunoprivileged sites such as the vitreous humor of the eye and the testes. The slow evolutionary rate of the genome during such persistent infections – 6 times less than occurs during human to human transmission – implies a very low level of replication. It is remarkable that Ebolavirus retains infectivity for such long periods with so little reproduction.

Such persistent Ebolavirus infections are of concern as they may lead to new outbreaks after many years. The frequency of such persistence can reach 75% of men at 6 months after infection. Antiviral drugs should be developed to eliminate persistent infections in individuals who have recovered from Ebolavirus disease. Individuals harboring virus in semen are easy to identify, but detection of virus in the eye – done by sampling the vitreous humor by needle inserted into the eye – will be more difficult to accomplish.

Trial By Error: Biopsychosocial Brigades Seek Traction with Long Covid

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By David Tuller, DrPH

Last week, two major articles on long Covid appeared in well-known US publications—one in the Atlantic, the other in Vox. Like the New York Times Magazine article that ran in January, these stories addressed with nuance the complex and unclear relationship between the varieties of long Covid and the group of entities collectively known these days as ME/CFS. They did not presume patients in either category were suffering from psychogenic symptoms.

Today, The New York Times ran an opinion piece from two women who helped spark the patient-directed long Covid movement. In their piece, Fiona Lowenstein and Hannah Davis made these pertinent observations about some of the inadequacies of the societal response to long Covid:

“We’ve seen this before with myalgic encephalomyelitis, also known as chronic fatigue syndrome. Because ME/CFS, as it is also called, is difficult to diagnose, many patients have gone uncounted, and research into treatments and cures remains underfunded compared to other illnesses. As a result, clinicians tend to be undereducated and patients are less likely to receive adequate care and government support. There’s a risk of repeating this cycle with people with long Covid.”

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The UK is still arguing over graded exercise therapy…

In the UK, much of the discourse has been different, so reading stuff from both sides of the Atlantic can be disorienting. Of course “exercise”–in the sense of “movement”–is being discussed and debated. It is a standard component of rehabilitative strategies, and variations of “exercise” for the range of long Covid presentations are being explored—although no one has a real clue about what’s going on for many or most of these patients. .

What I haven’t noticed in the US is this specific obsession with and controversy over graded exercise therapy (GET). This intervention, at least as designed for ME/CFS, attributes the perpetuation of the symptoms to deconditioning rather than any ongoing organic illness.

Aren’t we all bored with this already? Hasn’t the PACE trial testing this approach to ME/CFS been debunked? Why am I discussing this again? Because the biopsychosocial ideological brigades appear to have mounted a spirited campaign against the forces undermining their former hegemony in this field of medicine. Even Professor Peter White, the Queen Mary University of London psychiatrist and one of the lead PACE investigators, has reemerged from retirement to engage the naysayers. Professor White is one of three co-authors of a letter this week in The Guardian touting the benefits of GET for ME/CFS. For real!

The letter contained this doozy of a statement with no hint of irony or shame: “We know that graded exercise therapy is an effective treatment for chronic fatigue syndrome (or ME), a clearly related condition.”

It is hard to know how to respond to such a statement from Professor White. In the PACE trial, he and his colleagues reported GET to be “effective” only after rampant outcome-swapping. Re-analyses of the PACE data based on the investigators’ original outcome measures yielded either null results or very marginal benefits that wore off by long-term follow-up. It apparently needs to be repeated without cease that a study in which participants could be counted as “recovered” even if they got worse and in which 13 % of participants met an outcome threshold at baseline does not meet the minimal requirements for publication in any journal.

The Guardian letter is part of what seems to be a backlash emerging from some disgruntled folks against the UK’s National Institute for Health and Care Excellence, the agency that issues clinical guidelines for medical conditions. In November, NICE issued a draft for a new guidance that was three years in development. The draft categorically rejected GET or any interventions focused on increased activity and premised on the notion of deconditioning as a causative factor. It also rejected cognitive behavior therapy as a curative treatment, although it allowed for that and other approaches framed as supportive care.

An evidence review conducted for NICE as part of the guidance development process rated the quality of all the findings in support of GET and CBT as either “low” or “very low.” They applied a widely used system for this process called GRADE (for Grading of Recommendations Assessment, Development, and Evaluation). Since then, various luminaries in the biopsychosocial and evidence-based-medicine fields have assailed this negative assessment of the research base in statements posted on BMJ.com.

One group argued in an editorial that NICE’s findings were off because standard randomized controlled trials and GRADE are not the best way to assess complex interventions like those tested in PACE. One problem with that argument was that one of the editorial’s two co-authors had previously praised PACE as an excellent test of the interventions. (That was before PACE was publicly discredited. Oops!)

In a response, a second group defended the integrity of GRADE and assailed the authors of the editorial for not appreciating it. They argued that GRADE itself was fine but that the NICE team engaged in a “disastrous application” of the methodology. That these experts can’t agree among themselves about the reasons for their disapproval suggests they are flailing about for counter-arguments to the NICE draft that might stick—so far, without apparent success.

Those waging this debate over ME/CFS actually seem to be arguing about long Covid. The biopsychosocial brigadiers have been losing the argument over ME/CFS, given the questionable body of research they have produced and continue to cite. The NICE draft demonstrated that the tide was shifting in the other direction. With long Covid, they seem to be making much the same arguments over again—and simultaneously trying to un-write the last few years of critical debunking of the PACE approach. As the letter to The Guardian suggests with its call for a trial of GET for long Covid, they hope their efforts to reframe that narrative will help them gain footing and funding in a world awash with patients experiencing persistent and disabling symptoms after a viral illness.

Studies of all sorts of treatments for long Covid are of course warranted. However, the investigators responsible for much of the body of biopsychosocial ME/CFS research do not appear competent enough or knowledgeable enough about legitimate methodology and appropriate ethics to be entrusted with such an important mission.

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Is CBT different than the Lightning Process?

As a final point, I’m having trouble at this point understanding the distinction between the the PACE approach and the Lightning Process (LP). There is certainly a lot of cross-over among the investigators and experts. Professor Esther Crawley, Bristol University’s methodologically and ethically challenged pediatrician and grant rainmaker, conducted the methodologically and ethically disastrous trial of the LP for kids with ME/CFS. Professor Trudie Chalder, a CBT expert at King’s College London and a lead PACE investigator, has also been involved in LP research.

In a statement supportive of Professor Crawley’s LP trial, Professor Michael Sharpe, a psychiatrist at Oxford and another lead PACE investigator, drew favorable parallels between cognitive behavior therapy (CBT) and the LP. In Norway, proponents of CBT for ME/CFS are among those pushing for a new study of the LP. And Professor Paul Garner, an infectious disease expert at the Liverpool School of Tropical Medicine, has advised those with long Covid not to listen to sick ME/CFS patients and has directed them instead to Recovery Norway, a site full of LP testimonials. (Professor Garner was a co-signer with Professor White of the Guardian letter.)

As far as I can tell, the operating concept behind the PACE treatment approach and the LP are the same: Positive thoughts are good, negative thoughts are bad. Positive thoughts will heal you, negative thoughts will keep you sick. Being more active will also help.

That’s it. That’s the theory.

How vaccines work

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Vaccines work by educating the host’s immune system to recall the identity of a virus years after the initial encounter, a phenomenon called immune memory. Viral vaccines establish immunity and memory without the pathogenic consequences typical of a natural infection. The success of immunization in stimulating long-lived immune memory is among humanity’s greatest scientific and medical achievements.

Immune memory is maintained by dedicated T and B lymphocytes that remain after an infection has been resolved, and most activated immune cells have died. These memory cells can respond rapidly to a subsequent infection (Figure). Ideally, an effective and durable vaccine is one that induces and maintains significant numbers of memory cells. If the host is infected again with this same pathogen, the memory B and T cells initiate a response that rapidly controls the pathogen before disease develops. This paradigm is true for most human viruses for which vaccines exist, including measles, mumps, and varicella-zoster viruses and poliovirus. In some cases, antigenic variation, such as occurs with influenza virus, precludes complete protection by a memory immune response, necessitating re-vaccination.

Protection from Infection or Protection from Disease?

The memory response elicited by most human viral vaccines does not protect against reinfection, but rather against the development of disease. An individual may be exposed repeatedly to viruses and never be aware of it, because the memory response eliminates the virus before signs and symptoms develop. After vaccination with inactivated poliovirus vaccine, virus replication may take place in the intestine, but effectively blocks the development of poliomyelitis. On the other hand, the human papillomavirus vaccine is over 90% effective at blocking infection. Consequently the HPV vaccine induces sterilizing immunity.

Whether or not COVID-19 vaccines will block infection is unknown because it has not been adequately measured. The results of a few small studies suggest that some of the vaccines may prevent infection. However these studies are not conclusive because they are being done shortly after vaccination, when serum antibody levels are much higher than they will be in, say, 6 months. Only then will we have an accurate measure of how well vaccination blocks infection with SARS-CoV-2. I suspect that none of the COVID-19 vaccines will block infection, but will reduce virus reproduction sufficiently to impede transmission in the population.

Population-wide immunity (aka herd immunity)

To be effective, a vaccine must induce protective immunity in a significant fraction of the population. Not every individual in the population need be immunized to stop viral spread, but the number must be sufficiently high to impede virus transmission. Person-to-person transmission stops when the probability of infection drops below a critical threshold. This effect is called herd immunity.

The herd immunity threshold is calculated as 1- 1/R0. R0 is the number of nonimmune individuals that on average will be infected upon encounter with an actively infected individual. As the reproduction number, R0, increases the value of 1/R0 decreases, and thus 1 − 1/R0 gets closer to 1, or 100%. For smallpox virus, the herd immunity threshold is 80 to 85%, while for measles virus (which has a high R0), it is 93 to 95%. Early in the COVID-19 outbreak the R0 of SARS-CoV-2 was calculated to be 2-3, which would produce a herd immunity threshold of 50-70%.

Herd immunity only works when a vaccine either blocks infection, or sufficiently reduces virus reproduction in the host to impede person to person transmission. As stated above, I see no reason why COVID-19 vaccines will not sufficiently reduce transmission to enable herd immunity.

No vaccine is 100% effective at inducing immunity in a population. Consequently, the level of immunity is not equal to the number of people immunized. For example, when 80% of a population is immunized with measles vaccine, about 76% of the population is actually immune, well below the 93 to 95% required for herd immunity.

What about T cells?

For many virus infections, antibodies are crucial for preventing infection. However, resolution of infection often requires the action of cytotoxic T cells, which kill virus infected cells. For vaccines that do not induce sterilizing immunity, it is likely that T cells play a role in eliminating virus-infected cells and preventing the development of disease.

This division of labor has been largely ignored in the discussion of COVID-19 vaccines. Most of the dialog has concerned the induction of antibodies and their ability to neutralize virus infection. COVID-19 vaccines do induce virus-specific T cells and it is likely that these will clear infections that begin in vaccinated indivduals. It has been reported that amino acid changes in SARS-CoV-2 variants of concern do not affect T cell epitopes, and that T cell responses in individuals who have either recovered from infection or have been vaccinated are not affected by these changes. Therefore it seems likely that even if variants of concern are able to overcome to some degree previous antibody immunity, they will be cleared by T cell responses, avoiding severe disease and death. The results of the phase III trial of the J&J COVID-19 vaccine support this presumption.

Trial By Error: Psychosomatics Journal Linked to PACE Authors Highlights Bias from Subjective Outcome

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By David Tuller, DrPH

The Journal of Pyschosomatic Research, a high-profile publication from Elsevier, has recently published an article relevant to long-standing arguments about trials that are both unblinded and reliant on subjective outcomes–like, say, the PACE study and related research into psycho-behavioral treatments for ME/CFS. This specific question–how to assess research quality when subjective outcomes are involved–is at the core of ongoing debates over both draft guidelines for ME/CFS from the UK’s National Institute for Health and Care Excellence and Cochrane’s contested review of exercise therapies for chronic fatigue syndrome.

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One and Done

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by Gertrud U. Rey

On February 27, 2021, the FDA issued an emergency use authorization for a third SARS-CoV-2 vaccine. The vaccine was developed by Janssen Pharmaceutica, a Belgium-based division of Johnson & Johnson, in collaboration with Beth Israel Deaconess Medical Center in Boston. Perhaps the most exciting feature of this new vaccine is that it only requires one dose to be effective in inducing an immune response.

The vaccine is named Ad26.COV2.S because it consists of a human adenovirus vector, with a DNA genome, into which has been inserted the gene that encodes the full-length SARS-CoV-2 spike protein (pictured). Ad26.COV2.S is similar to AstraZeneca’s vaccine, based on a different adenovirus, and with a slightly different version of spike, which is not yet authorized in the U.S. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Upon injection into a vaccine recipient, the vaccine vector should enter cells and serve as a code for host proteins to synthesize the SARS-CoV-2 spike protein from the inserted gene. Ideally, the spike protein will then act as an antigen to prime the immune system to recognize SARS-CoV-2 if it infects the body at a later time. 

Adenoviruses are particularly suitable as vectors for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate relatively large segments of foreign DNA, and because they infect most cell types without integrating into the host genome. However, because of the prevalence of adenovirus infections in humans, most people have adenovirus-specific antibodies that could bind and neutralize these vectors, thus rendering them less effective at stimulating antibodies to the inserted gene product. AstraZeneca circumvented this issue by using an adenovirus of chimpanzee origin that does not normally infect humans. The adenovirus used to make Ad26.COV2.S (Adenovirus 26) is of human origin; however, when tested, most people have very few antibodies that inactivate this adenovirus, compared to antibodies against other adenoviruses. Thus, potential Ad26.COV2.S recipients are less likely to have pre-existing antibodies to the adenovirus vector itself. To optimize Adenovirus 26 for use as a vaccine vector, Janssen investigators deleted the gene that regulates viral replication, thus ensuring that the virus vector cannot cause an infection in human cells.

During infection, the SARS-CoV-2 viral particle fuses with the host cell membrane; a process that is mediated by two main events: 1) a structural rearrangement of the spike protein from its pre-fusion conformation; and, 2) cleavage of the spike protein by a cellular enzyme called furin. Based on the knowledge that the pre-fusion, uncleaved form of spike is more stable and immunogenic, Janssen investigators also inserted two mutations into the spike gene: one that locks the translated spike protein into its pre-fusion conformation, and one that prevents its cleavage by furin.  

The FDA’s decision to issue an emergency use authorization for Ad26.COV2.S was based on safety and efficacy data from an ongoing Phase III clinical trial done in 39,321 participants who received either a single dose of Ad26.COV2.S or a placebo control. The trial was randomized, meaning that participants were randomly assigned to the experimental group receiving the Ad26.COV2.S vaccine, or the control group, so that the only expected differences between the experimental and control groups were the outcome variables studied (safety and efficacy). Randomizing trial participants eliminates unwanted effects that have nothing to do with the variables being analyzed. The trial was also double-blinded, meaning that neither the investigators nor the subjects knew who was receiving a particular treatment. Double-blinding leads to more authentic conclusions because they reduce researcher bias.

The basic findings of the trial were as follows:

  • side effects related to vaccination were mild to moderate; and
  • the vaccine was
    • 66% effective at preventing moderate to severe COVID-19 across all geographic areas and age groups (U.S., South Africa, and six countries in Latin America);
    • 72% effective at preventing moderate to severe COVID-19 across all age groups in the U.S.; 
    • 85% effective at preventing severe disease; and
    • 100% effective at preventing COVID-19-related hospitalization and death as of day 28 after vaccination.

The apparently reduced efficacy of Ad26.COV2.S compared to the Moderna and Pfizer vaccines has led to considerable public skepticism. However, this is an unfair comparison for several reasons. Ad26.COV2.S was tested at a time when more variants were in circulation, including in places where the Moderna/Pfizer vaccines are thought to be less effective against locally circulating variants. Some limited data also suggest that Ad26.COV2.S might protect from asymptomatic infection and may thus prevent transmission from vaccinated individuals to non-vaccinated individuals. Although there is some evidence to suggest that the Pfizer vaccine has a similar effect, no such data exist yet for the Moderna vaccine.

The most critical measure of a vaccine’s efficacy is how well it prevents severe disease, hospitalizations, and deaths, and in this regard, all three vaccines are comparable. Moreover, Ad26.COV2.S has at least two advantages over the Pfizer/Moderna vaccines: 1) it does not require a freezer and can be stored in a refrigerator for up to three months; and, 2) it can be administered in a single dose. This will increase vaccine uptake, because people won’t have to get two shots and/or remember to get the second shot.  It also makes it easier to immunize people with limited access to healthcare, such as the homeless and people living in remote areas. When all these factors are considered together, it is clear that Ad26.COV2.S will be a crucial additional tool in the fight against this pandemic.

Trial By Error: A Q-and-A with Tracie White, author of The Puzzle Solver

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By David Tuller, DrPH

Tracie White, a science writer at Stanford University, first stumbled across the story of Whitney Dafoe as an assignment from one of her editors. That initial encounter ultimately turned into The Puzzle Solver: A Scientist’s Desperate Quest to Cure the Illness that Stole His Son, an account that Kirkus called “a complex, well-related story of medical detective work.”

The story of Stanford geneticist Ron Davis and his son Whitney’s severe case of ME/CFS was certainly not unknown, given previous coverage–starting with Miriam Tucker’s excellent 2015 feature in The Washington Post. White’s is the first full-length account. During the reporting of the book, she grew close to the family, which included psychologist Janet Dafoe, Whitney’s mom, and his sister Ashley. I asked White a few questions about the process of writing the book.

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