Francesca Tomasi received her B.A. from the University of Chicago and currently researches tuberculosis metabolism and drug targets.
Before the turn of the century, it lived virtually in oblivion. Now, it costs over $1 billion per year to treat in the US alone, it is a global public health problem, and every summer during tick season people are warned about its chronic symptoms. What is Lyme disease, why does it cause so much morbidity, and what can we do to protect ourselves?
Borrelia burgdorferi is a species of bacteria known as a spirochete, for its corkscrew-like shape. The organism itself is named after Willy Burgdorfer, a medical entomologist who first isolated B. burgdorferi in 1982. This tiny little pathogen is the causative agent of Lyme disease, along with a few other Borrelia species, and its life cycle moves between ticks and vertebrates. The bacteria reside within ticks, which then feed on vertebrates, thereby transmitting the bacteria to a new host in which they can carry out the rest of their life cycle. When another tick feeds on this host, it ingests more Borrelia, and the cycle continues. While humans tend to be dead-end hosts, since we take antibiotics for Lyme infections and engage in anti-tick behavior (long sleeves, tick checks, and repellent), human to human transmission has been well-documented via blood transfusions.
Borrelia infection is associated with symptoms resembling those of rheumatoid arthritis: namely, joint and muscle pain. Severe fatigue and neurological disorders like numbness, weakness, and cognitive impairment may also occur, increasing in severity and complications if an infection is left untreated. Progressed neurological symptoms like facial palsy, irregular heart rhythms, and meningitis have been reported in extreme cases. Currently, the CDC estimates approximately 30,000 cases of Lyme disease in the US, emphasizing that only a fraction of infections are actually reported. In fact, recent studies place case estimates closer to between 296,000 and 376,000 cases per year in the United States, and at least 85,000 more in Europe.
Lyme disease, as mentioned above, is curable with antibiotics. When treated early and for two to four weeks with doxycycline, amoxicillin, or cefuroxime axetil (all oral antibiotics), individuals typically recover fully and quickly. Patients with more progressed neurological or cardiac symptoms may receive intravenous antibiotics like penicillin, but they, too, usually recover.
Something known as post-treatment Lyme disease syndrome (PTLDS) may also occur, though. In this case, patients treated for Lyme disease have lingering symptoms for weeks to months after treatment. While the exact causes of PTLDS are unknown, many experts believe that damage incurred on tissues and the immune system during infection contribute to these persisting symptoms. The CDC does stress that long-term antibiotic regimens for Lyme disease are not correlated with improved recovery rates; rather, long-term use of these antibiotics is often associated with negative side effects and additional complications.
The Solution, Part I
In the 1990s, GlaxoSmithKline (GSK; then known as SmithKline Beecham), came up with an effective immunization against Borrelia infections. The vaccine mimicked a bacterial surface protein and primed the immune system to produce antibodies against it. And rather than waiting for Borrelia to enter a human host before antibodies could attack, the moment an infected tick bit an immunized individual, it would swell with antibody-laden blood that subsequently attacked any Borrelia residing within the tick.
The vaccine, called LYMErix, successfully passed phase 3 clinical trials (which involved nearly 11,000 volunteers) and gained FDA approval in 1998. It was a three-dose vaccine with up to 80 percent effectiveness, and it entered the market with a few caveats. To start, 80% efficacy means that one fifth of fully immunized individuals could still get Lyme disease if exposed. Furthermore, a multi-dose vaccine is inherently more difficult to implement on a large scale than a single-dose one, since each visit has to fall within a certain time period. For LYMErix, the second dose had to be administered one month after the initial dose, and the third dose at the one-year mark. Medical reviewers have also pointed out that GSK’s phase III trials failed to include young children, who are particularly high-risk for getting caught between ticks and developing Lyme disease.
What’s more, LYMErix was only effective against B. burgdorferi – this is the predominant Lyme-causing Borrelia species in North America, but for international subspecies the vaccine would not be helpful. Lastly, just as someone on malaria prophylaxis is more likely to be a little less careful about getting a mosquito bite, individuals immunized against Lyme disease were less likely to engage in the more immediate tick prevention efforts named above. This change in behavior not only increases risk of Lyme disease (especially without a 100% effective vaccine), but it also shoots up the risk of other serious tick-borne illnesses such as babesiosis and Rocky Mountain spotted fever.
Of course, the last point is not a direct side effect of LYMErix but a basic consequence of human behavior. As with the vaccine’s other limitations, advisory boards decided that the benefits outweighed the risks in Lyme-endemic regions such as the northeastern United States. The Advisory Committee on Immunization Practices, however, did not recommend LYMErix for people in low-risk regions, young children, and elderly adults, similarly to more recent decisions made concerning a novel dengue vaccine.
Disaster struck in the form of a class-action lawsuit in Philadelphia, Pennsylvania. Over 100 individuals filed for this suit, claiming adverse effects from LYMErix. The FDA was forced to re-examine adverse reactions reported from the vaccine trial as well as in more recent immunizations. It found that while approximately 26.8 percent of LYMErix recipients experienced soreness, redness, or swelling at the site of injection, only 8.3 percent of controls (individuals who received a placebo injection). These side effects are harmless, though, as they pass within three days without any treatment.
Ever notice how your arm often gets pretty sore after a flu shot? Vaccines like LYMErix and flu shots are typically injected intramuscularly, meaning deep within the muscle, which allows them to enter the bloodstream very quickly to begin priming an immune response. It is therefore natural to experience some soreness or irritation around an injection site. And since your body is forced to fight something when you get a shot, it is also normal to experience the occasional fever or malaise for a day or two.
The main cause for concern surrounding LYMErix, however, was not a little bump, bruise, or two-day fever. Rather, individuals were reporting more systemic reactions such as joint pain. The FDA’s investigation found no significant difference between vaccinated and placebo groups when it came to these symptoms (1.3 percent versus 1.2 percent). The stipulation with these data, however, is that the clinical trial followed patients for only one year, which gave lawyers an edge: what might happen with LYMErix vaccination in the longer term?
By 2001, three years after LYMErix entered the market, over 1.4 million doses had been distributed throughout the US, the majority concentrated around New Jersey. Out of these 1.4 million, there were 905 reports of the self-limited reactions described above, and 59 of post-vaccination arthritis. The FDA’s analysis, however, found that arthritis incidence related to vaccination was similar to background arthritis rates in non-vaccinated individuals, and the supposed LYMErix-induced arthritis cases were not found to be temporally associated with second or third doses, and effect one would expect to see in an immune-mediated (dose or exposure-related) event. Hence, the FDA declared that GSK’s Lyme vaccine did not cause harm to patients.
Nonetheless, the damage was done the moment lawsuits were involved. By its fourth year on the market, demand for the vaccine had dropped irreconcilably and, faced with social pressure and media-propagated fears, GSK voluntarily discontinued LYMErix in 2002. The story of LYMErix has become for many a cautionary tale of the power of anti-vaxxers and false information. Since neither the FDA for GSK could definitely link the vaccine to significant adverse events, this may in fact have been what happened.
In 2002, after LYMErix was discontinued, cases of the illness rose by 40% in the United States. There are two lessons to be learned here. One is to weigh scientific validation: there are so many scientific and legislative controls in place when it comes to designing, approving, and implementing vaccines and vaccination programs. The second lesson is that, with or without a vaccine, preventive measures ought always to be a priority. This is true for cholera (filtering water, even through a sash), dengue fever and malaria (bed nets, mosquito sprays), Lyme disease (long sleeves, tick repellents) or any other infectious disease that can be prevented with minor behavioral changes and at minimal cost. Vaccines are rarely 100% effective. But who would argue that no protection at all is better than some?
It is during the past 15 years that Lyme disease has grown into an epidemic.
Let’s Try This Again
Last week, the French biotech Valneva announced FDA and European approval to move its new candidate Lyme vaccine into phase I clinical trials – testing safety and efficacy in people. Valneva’s vaccine works like LYMErix – targeting the OspA protein – but also takes into account OspA proteins in other Borrelia species for wider immune coverage. Valneva’s vaccine has a ways to go before entering the market – statistically, over 90% of vaccines that pass from animal trials into human trials fail in phase I – but the scientific community has openly asserted it is time for a new Lyme vaccine.
It cannot be done without public support, though. The pharmaceutical industry, like any business, is extremely reliant on demand for production. Infectious disease treatments aren’t exactly money-makers the way other drugs like Lipitor or Plavix are. It is difficult to incentivize companies to pour billions of dollars and hundreds of thousands of hours into fighting pathogens unless there is a visible, imminent threat (for example, an airborne Ebola-like virus ripping across the globe). Lyme disease is a serious problem, though, stealthy as it might be, and with changing climates and environments, its public threat is only expected to grow.
Francesca Tomasi received her B.A. from the University of Chicago in Biological Sciences and currently studies tuberculosis metabolism and drug targets.
I read an article yesterday by Arthur Caplan, head of medical ethics at the New York University Langone Medical Center. His piece is called “How the Zika Virus Outbreak Foretold Donald Trump’s Win.” I have to admit I was skeptical when I first read the title, and I braced myself for a depiction of some far-fetched relationship between Republicans and mosquitoes. I thought I was about to read another straw-grasping piece aimed at justifying this year’s failure for most major election forecasters. I was wrong about the far-fetched correlations and grasping at straws, but I was correct about the latter point. Dr. Caplan does try to explain why the media – and society as a whole – failed both to forecast Donald Trump’s victory and understand the Zika virus. He does so in a thought-provoking and, in my opinion, unnervingly accurate way.
Two weeks ago, the World Health Organization declared that Zika virus is no longer a public health emergency of international concern. Dr. Caplan repeats this announcement, and goes on to say that most people simply read the headline and proceeded to breathe a sigh of relief with the end of a Zika-filled year, a lot like with Ebola in 2014. Re-tweet the headline, re-post the link, the end. “Well, that wasn’t as bad as I thought it was going to be, was it?”
Global health, a discipline as scientific as it is social, as basic as it is intricate, cannot even begin to be fully discussed with a 140-character limit (Twitter), a 10-second time limit (Snapchat), or even the approximate 20-minute attention span of the average adult (which is rapidly shrinking).
The significance of the WHO’s change in designation for the virus is not that Zika is over, or that we have it fully under control, or that all the travel advisories are going to go away just in time for the holidays. Zika no longer being a public health emergency signifies that it has become more than that: it is now endemic in multiple regions, and these areas need to direct their efforts against long-term effects of the virus. Preparation means money; and since, as Dr. Caplan explains, emergency money is about to run out, the WHO needs “to pivot to allocate funds from other sources.” Hence the status change.
Multiple news sites, including this Washington Post article, got it right. The media outlets that did not have to constrain their stories into ten-second bits supplemented their headlines with cautionary words like these: “But the change in designation does not represent a downgrading of Zika’s importance, officials said.” David Heymann, the head of the WHO emergency committee on Zika, said the change “represents an escalation into a major activity within WHO. If anything, it’s escalated in importance.” Just because the Washington Post or CNN had the space to explain this and the quotes to support it, however, does not mean everyone listened.
Dr. Caplan goes onto say that, of course, underreporting or under-reading are not the only reasons for lapses in understanding. They are, however, extremely important ones, especially when the right information is out there. “All in all,” he writes, both with Zika and the elections, people “didn’t get the whole story” because they only read tweets, or heard about them from other people. Messages were superficial and stories were incomplete. “Because human beings are prone to such selective attention, especially in today’s world of information overload…we see punchy, easy-to-understand language dominating thoughtful analysis of issues.” For this reason, Dr. Caplan argues for increased attention from readers, and increased commitment from news outlets.
This trend – of lagging attention and snaps of fragmented information – might be more pronounced now because of the rapid pace of today’s world, but it certainly is not unique to this decade. Paul Farmer made the same general argument nearly 18 years ago.
Infections and Inequalities is a book published in 1999 by the anthropologist-physician Paul Farmer. Dr. Farmer is a co-founder of Partners in Health, an organization whose mission is “to provide a preferential option for the poor in health care…[b]y establishing long-term relationships with sister organizations based in settings of poverty….to bring the benefits of modern medical science to those most in need of them and to serve as an antidote to despair.”
Simply put, Dr. Farmer’s overall thesis is that chronic infectious diseases – such as tuberculosis and HIV, which he discusses in-depth – are just as microbiologically-driven as they are propagated by social inequality. “Inequality itself constitutes our modern plague,” Dr. Farmer writes, and he has anecdotes and data to prove it.
Infectious and Inequalities asks and answers many questions, engaging readers in thought experiments that link local contexts and socioeconomic conditions with national crises. The content of his book is enough for many future articles, but one point he makes resonates with Dr. Caplan’s depiction of today’s headline skimmers. It comes with his revisit of the true meaning of “re-emerging” infectious diseases.
I have written about tuberculosis before. As a microbiologist, I study TB every day in my lab. In my own work, I have called it a re-emerging infectious disease because, once thought to be conquered with the discovery of antibiotics like rifampicin in the mid-twentieth century, Mycobacterium tuberculosis prevalence is increasing once more today, and so is its resistance to common first- and second-line drugs. The social stigma clouding tuberculosis across the world also has a clear effect on disease dynamics. I should have ended my pieces with “...in America.”
In his book, Dr. Farmer says that tuberculosis is not re-emerging at all. Instead, he argues that the notion of “re-emerging” is more often about perspective – or more specifically, a lack thereof. He writes, “From our clinic in central Haiti, it is impossible not to regard the notion of ‘tuberculosis resurgence’ as something out of a cruel joke – or yet another reminder of the invisibility of the poor.” While TB may have lurked in the shadows through the turn of the century in America and other developed parts of the world, TB persisted in impoverished countries like Haiti. There was no “re-emergence” of TB in Haiti when we saw a rise in cases in the US last year; there was just the same endemic TB that had gone unnoticed for decades.
Dr. Farmer explains that tuberculosis’s invisibility the last several decades requires an examination of “disease awareness – that is, of consciousness and publicity.” Tuberculosis was not in the headlines for the latter half of the twentieth century because the places writing headlines were unaffected. Complacency with TB therefore washed over the majority of the developed world, since it was never in the news. It was assumed conquered. “In short the ‘forgotten plague’ was forgotten in large part because it ceased to bother the wealthy.”
Now, awareness of tuberculosis is on the rise thanks to public service announcements, an increase in international coverage and public health outlets, and of course the fact that drug-resistant TB is starting to affect some developed countries again. “The story,” Dr. Farmer continues, “ends up as ‘Tuberculosis is Back’ rather than, more appropriately, Tuberculosis is Back in the News.’” While Dr. Caplan faults readers in his article for their cursory skim over titles to form inaccurate conclusions, Dr. Farmer instead puts responsibility on the sources themselves. “We live in the world where infections pass easily across borders – social and geographic – while resources, including cumulative scientific knowledge, are blocked at customs.”
Put together, today’s headline readers and yesterday’s headline ignorers are responsible for the same thing: stagnant situations. In the case of tuberculosis, what do we get when we only have semi-permeable borders of information instead of fully permeable ones? “Two things at once,” Dr. Farmer writes. “A completely curable disease and the leading cause of young adult deaths in much of the world.” In the case of Zika, we get the misconception that it is no longer a big deal.
Reading the headline “Zika is No Longer a Public Health Emergency” without understanding that it’s because Zika is now here to stay as a long-term issue, is instilling complacency in skimmers about the actual state of the virus. Likewise, not producing headlines like “Tuberculosis is Still Disproportionately Killing Haitians” instills complacency in the actual state of this pathogen and, more broadly, of marginalized populations. This lack of communication is unfair and, as Dr. Farmer says, unethical, because we are “leaving a vast ‘control group’ of unfortunates to exhibit the natural history of untreated disease.”
We need to resume making time to read full stories instead of just fitting headlines between sips of coffee. We also need to start finding headlines where nobody else is looking. We then need to write these stories, and read them, and discuss them, and engage in ways to fix them. And that is my goal moving forward with Infective Perspective: to tell the stories no one else will, and to encourage readers to contribute and do the same.
I’m going to end with one of my favorite quotes from Infections and Inequalities, and one that I have communicated many times – though perhaps less eloquently – on Infective Perspective. “Microbes, and their vectors, recognize none of the artificial boundaries erected by human beings. Theirs is the world of natural limitations: temperature, pH, ultraviolet light, the presence of vulnerable hosts, and mobile vectors.” A pathogen in one pocket of the globe can make its way to any other in a matter of hours or days, and this is a natural result of today’s massively inter-connected world. While people argue this is a problem for public health, such as with the spread of SARS in 2002, our interconnected world really just makes it no longer excusable to block the flow of medical and public health information. Thus, if a germ does cross national borders, whatever country it ends up in ought to have access to the proper tools and knowledge to curb a real problem, and without sparking an emotional roller coaster in the media.
Nick received his B.S. in Biology from the University of Notre Dame and currently studies the spread of drug-resistant malaria.
While sci-fi depictions of genome editing portray parents custom-designing their children, biomedical scientists are excited about a much more pressing application: treating and preventing genetic diseases. Here’s how infectious diseases may be impacted.
Scientists have been intentionally manipulating animal genomes ever since Hermann Muller discovered that x-rays cause mutations in fruit flies back in 1926. Human-directed selection of domesticated plants and livestock goes back further by several thousand years. However, the advent of modern genetic engineering using programmable nucleases has opened the door to precise modification of human genes.
This is standard practice in laboratories all around the world that culture immortalized cell lines derived from humans. Genes in these cells are deliberately mutated so that scientists can determine how specific changes affect the cells’ phenotype: for example, how the cells respond to certain drugs or pathogens. What’s new is that scientists have recently succeeded in precisely editing the genomes of human embryos. While still extremely difficult and tightly regulated, this research raises ethical concerns about which genes should be open to modification, if any.
Nevertheless, genome editing research will proceed, however slowly, and at first will likely focus on human genes associated with severe diseases. If scientists tried to engineer the healthiest possible human, what would it look like? Heritable conditions caused by mutations in just one gene (cystic fibrosis, for example) are ideal first targets in editing people’s genomes due to the simplicity of their genetic cause. In addition, there are genes that come to mind when considering the effect human genome editing might have on infectious disease transmission. The two highlighted here are involved with protection against HIV and malaria, respectively.
Burden: 1.1 million deaths, 2.1 million new infections in 2015 (AIDS by the Numbers)
Target for editing: CCR5 gene
In 2008, Timothy Ray Brown, also known as the Berlin patient, was cured of HIV when he received a transplant of hematopoietic stem cells (HSCs) from a donor with something called the CCR5-Δ32 mutation. This means Brown’s donor had a congenitally inherited deletion of 32 nucleotides in the gene that codes for C-C chemokine receptor type 5 (CCR5), a protein normally displayed on the surface of immune cells derived from HSCs. It also means that, due to the deletion, Brown’s new immune cells had defective CCR5 proteins. Because the majority of HIV viruses worldwide, including Brown’s HIV-1 type, recognize CCR5 on human immune cells and use it to invade their host, people with defective CCR5 have increased protection from HIV infection. After the injection of new HSCs, the HIV in Brown’s body could no longer recognize cells that it could invade and replicate in, and he was cured.
Because protection is conferred by a simple 32 base pair deletion in one gene (for reference, the human genome contains approximately 3 billion base pairs), it is theoretically an easy target for editing. In April, scientists did just that. The team introduced the CCR5-Δ32 allele into non-viable human embryos using the CRISPR–Cas9 gene editing system. The embryos used in this experiment, known as 3PN, would otherwise normally be discarded, as they were the result of abnormal fertilizations of two sperm cells joining with a single egg which precludes proper development in vivo. However, the editing only worked in 4 of 26 attempts, and even then the embryos were mosaics, meaning some cells in the embryos retained normal unedited copies of CCR5 rather than exclusively incorporating the new version. But if improvements to the gene editing process are made and it becomes widespread in the future, scientists may again turn to CCR5 as a target for gene editing, which could prevent or cure millions of HIV infections. Additionally, CRISPR may be used to cure HIV patients by removing virus DNA that has integrated into the host genome.
Disease: Malaria (Plasmodium vivax)
Burden: 1,400 to 14,900 deaths (estimated), 13.8 million cases in 2015 (World Malaria Report 2015)
Target for editing: Duffy blood group antigen gene (DARC)
The characteristic alternating fever and chills of malaria are caused by Plasmodium parasites that infect our red blood cells (RBCs). Although the vast majority of malaria deaths are caused by the species Plasmodium falciparum, another species, P. vivax, causes a huge amount of morbidity from the Americas to Southeast Asia. Interestingly though, P. vivax malaria is conspicuously absent from most of sub-Saharan Africa, an otherwise malaria-rich region.
The people that live here show a high degree of resistance to P. vivax infection because they contain a genetic mutation that prevents a protein called the Duffy blood group antigen from being expressed on the surface of their RBCs. These people are dubbed Duffy negative. Normally, P. vivax parasites recognize the Duffy antigen as a receptor for infecting RBCs (similar to how the HIV-1 virus uses CCR5), so without that protein, Duffy-negative individuals are protected from infection. The Duffy negative phenotype can be conferred with a single point mutation in the DARC gene, a theoretically simple change to engineer.
However, there are compelling reasons to think twice before attempting to edit the DARC gene. For one, reports of P. vivax infection in spite of Duffy negativity are on the rise across the world, suggesting parasite evolution. Additionally, the Duffy negative phenotype has been associated with increased risk for prostate cancer and HIV susceptibility, among other drawbacks.
As with most new therapies, therapeutic human genome editing is likely to be very expensive for the consumer. Unfortunately, the overwhelming burden of the two diseases above is on the very poorest of people across the world. These people may not even have access to proper drugs, much less the advanced and tailored theoretical treatment with genome editing.
The good news is that human genome editing is probably not the best current solution to combat HIV and malaria anyway. Continued development of drugs and vaccines and increasing health and urban infrastructure in low-income countries is a much more attainable goal. Preventive measures like increased deployment of bednets for malaria and condoms for HIV will also go a long way to combatting these diseases. Interestingly, in the case of malaria, it appears that releasing genetically modified mosquitoes that are unable to transmit disease is much closer on the horizon than human editing. If the sci-fi “designer baby” scenario of the future does come to actualization, then perhaps someday there will be large-scale editing of the human CCR5 and DARC genes. For now, though, human genome editing remains just a controversial but exciting area of research.
Prospects and challenges in therapeutic genome editing (Open Access): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492683/
A very readable guide to genome engineering with programmable nucleases, including ZFNs, TALENs, and RGENs:
Search for genes related to disease outcome: http://www.omim.org/