Current law would make Medicare a much less generous payer for physicians in future decades than private health insurers may be, newly released government reports show. That could put pressure on Congress to boost federal funding for care of senior citizens and people with disabilities.
In addition to sounding their much noted annual warning on the state of Medicare’s hospital funds, the trustees and staff of the giant federal healthcare program on Monday emphasized an uncertain future for the current approach to physician payments.
In their annual report, the Medicare board of trustees cited 2026 as the year when the federal Hospital Insurance (HI) Trust Fund is likely to be depleted. This is the same date that the trustees gave in their 2018 report for this key source of Medicare’s hospital payments to be exhausted, although the outlook is even worse this year.
By 2026, HI revenue would be sufficient to pay only 89% of the costs covered by the fund, the trustees said on Monday. In their 2018 report, they said the fund might cover 91% of these costs by then. Experts predict lawmakers will step in to prevent these cuts.
“Since seniors vote, before we get to this point, Congress almost certainly will enact some policy that will push the insolvency date out a few years,” Joseph Antos, a researcher at the American Enterprise Institute, told Medscape Medical News in an email exchange.
“If history is a guide, we’ll never actually hit a year when Part A is insolvent,” said Antos, who earlier worked at the Congressional Budget Office and the White House’s Office of Management and Budget. “Little fixes are possible, and of course, actuarial projections are only predictions.”
The release of the annual trustees’ report has for many years generated headlines about Medicare going broke. That description irritates experts in the finances of the federal program.
The hospital trust fund involves less than half of the Medicare program, not taking into account Part B, which covers physician services, or Part D, which covers pharmacy bills, said Charles Blahous, a researcher at the Mercatus Center at George Mason University, who is a former member of the board of trustees of Medicare and the Social Security Administration.
“The insolvency date is a minor part of the story and really shouldn’t be the main focus of concern,” Blahous told Medscape Medical News. “There are enormous financial strains above and beyond those which are captured in the insolvency date.”
Payments “Not Achevable”?
Federal officials seem to agree with this view.
Routinely accompanying the trustees’ report is an analysis by staff of the Centers for Medicare & Medicaid Services (CMS). Titled “Projected Medicare Expenditures Under an Illustrative Scenario With Alternative Payment Updates to Medicare Providers,” this report delves into questions about how much the program might cost if Congress were to override its own previous efforts to control its spending.
The 2019 version of this CMS report notes that lawmakers will in the years ahead feel pressure to revisit recent laws that may curb growth in the program’s spending.
The combined effects of the 2010 Affordable Care Act and the 2015 overhaul of physician pay, known as the Medicare Access and CHIP Reauthorization Act (MACRA), dictate “substantial, but very uncertain, cost reductions” for many services, CMS staff wrote in the 2019 version of this analysis.
Medicare payment levels could slip from equaling about 75% of private health insurance in 2017 to below 60% by 2030 and then drop close to 40% by 2050, according to a chart in the report. Medicare payment then might slide to 23% of private insurance rates by 2093, wrote John D. Shatto, director of the Medicare and Medicaid Cost Estimates Group, and M. Kent Clemens, an actuary, who authored the report.
Shatto and Clemens said there is a “strong likelihood that the scheduled physician payment updates and the productivity adjustments will not be achievable in the long range.
“It is reasonable to expect that Congress would find it necessary to legislatively override or otherwise modify the reductions in the future to ensure that Medicare beneficiaries continue to have access to health care services,” they wrote.
If that happens, “actual Medicare expenditures are likely to exceed the projections shown in the 2019 Trustees Report for current law, possibly by considerable amounts,” Shatto and Clemens added.
In their report, the trustees noted that Medicare expenditures were $741 billion in 2018 and were set to grow in future years at a faster pace than either workers’ earnings in general or the economy overall.
Expressed as a percentage of the gross domestic product, Medicare expenses could increase from 3.7% in 2018 to 6.5% by 2093, as determined on the basis of a so-called intermediate set of assumptions, the trustees said.
But it could rise to 9.0% in 2093 if “the relatively low price increases for physicians and other health services under Medicare are not sustained and do not take full effect in the long range as assumed in the illustrative alternative projection,” the trustees said.
In the view of the trustees, Medicare spending at this level thus would “substantially increase the strain” on taxpayers, the economy, and people enrolled in Medicare.
Time Left
Physician associations, such as the Medical Group Management Association (MGMA), will continue to monitor Congress for any sign of a change in approach to payment.
Anders Gilberg, MGMA’s senior vice president of government affairs, said his organization is concerned that physician payments could prove “a political path of least resistance for Congress to find savings in Medicare.”
But he also does not see lawmakers taking a serious look at Medicare finances.
“Despite these dire forecasts, there isn’t an indication that Congress will address entitlement reform near term,” he told Medscape Medical News in an email. “The current political debate is focused on expanding Medicare, not stabilizing its finances.”
At this time, the supply of physicians available to provide care for the roughly 60 million people enrolled in Medicare appears adequate.
Congress relies on its Medicare Payment Advisory Commission (MedPAC) to keep tabs on how easily people enrolled in the program can find physicians. In March, MedPAC told Congress that its research indicated that 70% of people enrolled in Medicare reported they never had to wait longer than they wanted for routine care, and 79% reported having easy access to care of an illness or injury.
In fact, MedPAC research suggests that only 64% of those with private insurance were similarly satisfied with their access to routine care and that 74% of them were similarly satisfied with their access to care for illness or injury.
Congress thus seems unlikely to soon revisit the issue of Medicare pay for physicians to a significant extent, said Juliette Cubanski, PhD, MPP, MPH, associate director of the program on medicare policy at the nonprofit Kaiser Family Foundation. Lawmakers at this time are more engaged with other topics, such as reining in pharmaceutical prices.
“There are more immediate concerns that Congress is trying to act on right now,” Cubankski told Medscape Medical News. “Taking on an issue like Medicare solvency or physician payment rates would probably be a more challenging topic for Congress to rally around and find bipartisan agreement,” she said.
In their 2019 report, Medicare’s board of trustees did offer a note of optimism about the program’s fiscal outlook.
Projections of Medicare spending are “highly uncertain, especially when looking out more than several decades,” owing in part to the possibility of major scientific advances, they said.
“Some conditions that are untreatable today will be handled routinely in the future,” the Medicare trustees said. “While most health care technological advances to date have tended to increase expenditures, the health care landscape is shifting. No one knows whether future developments will, on balance, increase or decrease costs.”
Popular smartphone apps for depression and smoking cessation fall short when it comes to informing users of their data sharing and privacy practices, new research shows.
In a cross-sectional study of 36 top-ranked apps for depression and smoking cessation available in app stores, 29 (81%) transmitted data to services provided by Facebook or Google. But only 12 (43%) of 28 apps sharing data with Google and 6 (50%) of 12 apps sharing data with Facebook accurately disclosed this in a privacy policy.
“Informed choice is a fundamental principle in healthcare,” Kit Huckvale, MBChB, postdoctoral fellow at the Black Dog Institute, UNSW Sydney, Australia, told Medscape Medical News.
“What is concerning about our findings is that users of popular health apps often have no way to tell if Facebook or Google will be involved in handling their data in some way. Many people may not take issue with this. But everyone has the right to know and reach their own decision,” said Huckvale.
Twenty-five (69%) of the 36 apps evaluated did incorporate a privacy policy. Of these 25 apps, 22 of them (88%) told users how they primarily use the data collected, but only 16 (64%) disclosed other secondary uses for the data.
Huckvale believes providers who are recommending mental health apps to patients “should highlight — without overstating the risks — the high likelihood of data sharing with these companies. This is also a timely opportunity for providers to ensure that their own products accurately disclose any third-party data handling.”
Huckvale said calls for further regulation of the health app marketplace are “understandable but run into problems of feasibility given the sheer numbers of apps. Nor is more legislation necessarily needed. Consumer privacy law is generally clear in this area, and companies such as Facebook and Google already require developers to clearly state the use of their services in privacy policies,” he said.
Nevertheless, there are some opportunities for action, said Huckvale.
“Focussing on the quality of the smaller numbers of apps that are most likely to be used in clinical practice is a promising area. Curated app collections, such as those offered by PsyberGuide for mental health and the UK NHS, make it feasible to scrutinize apps in depth.
“But, as our study shows, this only works if you can reliably explore the detail of what apps are doing with data — just looking at privacy policies isn’t enough,” Huckvale said.
Huckvale also believes the clinical and research community needs to “get better at communicating to developers these kinds of safety and privacy-related priorities — and why we care about them in the first place.”
Cause for Concern
Commenting on the study for Medscape Medical News, Adam C. Powell, PhD, president of Payer+Provider Syndicate, a Boston, Massachusetts–based consulting firm specializing in operational challenges faced by health insurance companies and hospitals, said the finding in this study that app privacy policies often misrepresent the underlying privacy practices of apps is “quite concerning.”
To address the problem of privacy policy inaccuracy, there needs to be some degree of third-party oversight, said Powell. He noted that between 2002 and 2018, the Federal Trade Commission (FTC) brought 65 cases against companies that engaged in unfair or deceptive practices involving the use and protection of consumers’ personal data.
However, the FTC probably can’t be the sole enforcer, said Powell, adding that there is likely a need for other third parties to assist in the app review process. “Such organizations could be non-profit third parties, such as PsyberGuide, government-run entities, such as the NHS Apps Library (run by the UK), or even for-profit entities,” he noted.
“Rather than conducting enforcement actions against problematic apps, these third-parties can and do play a role in curating lists of high-quality apps. Privacy policies need to be one element considered within the curation process,” he added.
Powell also noted that inadequate disclosure about data sharing is a small part of a larger problem surrounding privacy policies. In a recent study, he and his colleagues found that most privacy policies for mental health apps are written at a college reading level.
“Thus, even if it is possible for regulators to enforce truth in privacy policies, they may not play an important role in shifting behavior if they are too complex for people to understand, or if they take too long to read for most people to consider them,” Powell said.
The study had no commercial funding. The study authors and Powell have disclosed no relevant financial relationships.
JAMA Netw Open. Published online April 19, 2019. Full text
Walgreens Boots Alliance Inc. will raise the minimum age required for customers to buy tobacco products in its stores to 21, up from 18 in most states, as the drugstore chain faces pressure over its cigarette sales from federal regulators, activists and some investors.
The new chainwide policy will start Sept. 1, the company said Tuesday. Walgreens’ move is its most recent step in its effort to further prevent youth access to tobacco products, including a policy implemented last October that requires verification regardless of age, the company said.
“We’ve seen positive results from other recent efforts to strengthen our policies related to tobacco sales, and believe this next step can be even more impactful to reduce its use among teens and young adults,” Richard Ashworth, Walgreens president of operations, said in a statement.
Walgreens’ new policy comes as the company has been publicly supportive of efforts in a number of states to raise the legal age to use tobacco to 21. Currently, about a dozen states have raised the tobacco buying age to 21, along with at least 450 localities, according to the Campaign for Tobacco-Free Kids, an antitobacco nonprofit.
While Walgreens continues to sell cigarettes in the vast majority of its 9,600 U.S. stores, the chain has been testing some tobacco-free stores and is encouraging employees in others to offer aids to quit smoking to customers buying cigarettes. The pharmacy chain has also reduced the visibility of tobacco products in some stores.
Unlike CVS Health Corp., which stopped selling tobacco products in 2014, Walgreens has continued to sell cigarettes, electronic cigarettes and other tobacco products in most of its stores, drawing criticism from federal regulators, lawmakers as well as activists who say that tobacco products don’t belong in a health store.
In February, the U.S. Food and Drug Administration called out the company out for being a top violator among pharmacies illegally selling tobacco products to minors. In response, Walgreens said that it has a zero-tolerance policy on selling tobacco to minors and any employee violating its policy is subject to termination.
Last week, Senate Majority Leader Mitch McConnell said he planned to introduce legislation raising the national minimum age to purchase tobacco products to 21 from 18. Sen. McConnell’s announcement followed the introduction earlier this month of similar bills in the House.
Altria Group Inc. and British American Tobacco PLC, the two biggest U.S. cigarette manufacturers, as well as e-cigarettes maker Juul Labs Inc., all support raising the age to 21. The hope is that the move would curb underage smoking and the use of e-cigarettes among youths.
Walgreens doesn’t sell tobacco products at a test store in Deerfield, Ill., near its headquarters, as well as 17 stores in Gainesville, Fla., as part of a 12- to 18-month pilot program it started last year. It also doesn’t sell cigarettes in Massachusetts, New York City and San Francisco, which have banned pharmacies from selling them. Outside North America, the company’s Boots pharmacies don’t sell tobacco products.
After a rough year for Bayer and Johnson & Johnson’s anticoagulant Xarelto, the companies hoped the competition would take it easy in 2019. Pfizer and Bristol-Myers Squibb’s Eliquis had other plans.
After totting up a 23% share of the field in the first quarter of 2019—the same share as 12 months ago—Xarelto continues to fall behind Eliquis, which gobbled up a whopping 39% of the warfarin alternative market in the first week of April, Credit Suisse analyst Vamil Divan wrote in a Monday investor note. And that follows a first-quarter sales report showing Xarelto’s increased list price was offset by discount pressure and competition, Divan noted.
With Eliquis expanding, what’s going on with Bayer and J&J’s declining blockbuster?
Divan said Xarelto has been the continued victim of aggressive U.S. price discounting and increased competition in recent years, a one-two punch that has offset the drug’s increased price. Part of that discounting frenzy has been tied to a 2018 Medicare policy change that has kept sales revenue low.
Sales of Bayer and J&J’s blockbuster warfarin alternative have flagged for six straight quarters while sales of Eliquis, which now boasts a 39% share of the market, have continued to grow. A third competitor, Boehringer Ingelheim’s Pradaxa, sits in third place with 3% despite being first to market.
In the week ending April 12, Xarelto reported more than 204,000 total prescriptions compared withnearly 343,000 for Eliquis. That equated to a roughly 5% drop in scripts week over week for Xarelto, according to IQVIA.
With competition stiffening for anticoagulants, aggressive U.S. discounting has knocked Xarelto for a loop, leading to stagnant growth projections from J&J, which called 2019 a “trough year” in an earnings call with investors last week. In the first quarter of 2019, the med’s sales slipped 6.3% to $542 million.
That drop is partially tied to a recent change in federal law known as the “donut hole” provision, which requires drugmakers to offer significant discounts to Medicare Part D coverage. Divan said the donut hole manufacturers’ discount will step up as high as 70% starting this year.
To counteract flagging sales, J&J has eyed Xarelto label expansions, but Divan said the effects of new indication approvals on the company’s sales would only be felt over the long term.
In October 2018, the FDA approved Xarelto’s use in coronary and pulmonary artery disease (CAD/PAD) that analysts said could rake in an additional $1.5 billion per year. However, Divan said the company was preaching patience with Xarelto’s expanding label, arguing that blockbuster sales in CAD/PAD could take years to materialize.
Chasing new indications is nothing new for Xarelto, and the CAD/PAD win follows a pair of major flops for the drug in blood clot and heart disease trials in October 2018. Despite less-than-rosy results in those trials, J&J continues to hold out hope Xarelto could earn an approval in both categories.
Prior to those hiccups, Bayer stopped a separate Xarelto trial in 2017 after treatment of stroke patients showed few benefits above aspirin for prevention of a second stroke or embolism.
Many scientists struggle with networking. If you’re one of them, don’t despair. A structured, scientific approach could be all you need.
Networking starts at home. Before you go to a conference or another event, identify a core group of people, likely to be there and whom you’d like to meet to advance your career. These might be potential collaborators, employers, funding sources or future conference programme organizers. Consider individuals who wrote the latest papers in your field, gave a memorable talk at a meeting or won major grants or awards.
Three goals for a networking event
After identifying this group, develop networking goals. When you attend an event, you shouldn’t leave the room until you have accomplished three things:
1. Introduced yourself to every person in your core group. Are you a scientist working on a technique they might find useful? Did you once work with one of their collaborators, mentors or trainees? Your aim should be that they remember meeting you.
2. Ensured that people in this core group know what specialty and industry you are in. Does your research expertise lie in cancer or neuroscience? Do you plan on having a career in academia, health care, industry, government or big pharma?
3. Made sure your new expanded network knows how to get a hold of you. You’ve exchanged business cards, added each other’s contact info into your phones or connected on LinkedIn.
Surviving a networking event
There are several ways to survive a networking event without inducing anxiety.
Arrive early. Arriving before the venue is noisy and full of people lets you get accustomed to the sights and sounds of the room before they become overwhelming. You can also scope out places to retreat to if you need a moment of solitude.
Arrive with a friend or colleague. Not knowing anyone is uncomfortable. Walking in with a friend guarantees you will know at least one person in the room who can introduce you to others in their network.
Have strategies to re-energize mid-event. Give yourself a networking time limit and then go somewhere to regroup in solitude. Or consider taking a break to peruse the books on the shelf or examine the artwork. Sometimes you just need to be seen and not heard at a networking event.
Have ‘starter’ and ‘closer’ sentences ready. Starting a conversation can be awkward. Have some opening sentences ready. “What a beautiful venue! Have you been here before? How long have you worked here? How has the conference been for you so far?” Having something benign to break the ice will come in handy.
Equally important is having sentences to conclude your discussion, allowing you to make a graceful exit. “I have to make a quick call”, or “I’m going to get a drink, would you like anything?”
What else can you do?
Conferences aren’t the only spaces to network. You can also look to:
Social media. Not all networking has to be done in person. It is acceptable to network online and to respond only when you’ve fully formulated your thoughts. Consider joining a distribution list or amplifying your voice on social media.
Networking outside formal events. If you find formal networking events draining, consider alternatives. Joining a committee or hosting a speaker at your institution can be effective, especially if you make the most of your strengths: are you great at idea generation, logistics or marketing? Offer to host a speaker at your institution and capitalize on the opportunity to communicate directly with the person through e-mail before the event, thereby avoiding awkward silence. You might find yourself feeling more comfortable on the day of the event, if you have already made conversation over e-mail and are on familiar ground. If not, ask someone who is more comfortable with face-to-face interactions and extemporaneous conversation to approach the speaker on your behalf on the day of the event.
Most people can be successful at networking, and awkward moments can be alleviated with a little preparatory work. Be prepared and give yourself time limits to mitigate undue stress. Find alternatives, such as social media and e-mail, which enable you to branch out in a controlled environment.
doi: 10.1038/d41586-019-01296-2
This is an article from the Nature Careers Community, a place for Nature readers to share their professional experiences and advice. Guest posts are encouraged. You can get in touch with the editor at naturecareerseditor@nature.com.
Like millions of people in the United States last year, Stanley Plotkin and his wife got vaccinated against influenza at the start of the Northern Hemisphere’s flu season, in early October. Plotkin, a physician and emeritus professor at the University of Pennsylvania, knew well the value of the shot: He is one of the world’s most renowned vaccinologists, having had a hand in several vaccines on the market, including the one for rubella. He’s even the co-author of the standard medical textbook, Vaccines.
In January, just 3 months later, the couple got a second flu shot.
That was an unusual choice, one not recommended by the U.S. Advisory Committee on Immunization Practices (ACIP), which guides the country’s vaccine usage. But a growing body of evidence that the protective immune responses triggered by flu vaccines wane in a matter of weeks persuaded Plotkin to return to the clinic. “The time and cost was trivial compared to the importance of influenza at my age,” says Plotkin, 86. “With flu, we’re not talking about getting a case of the sniffles.”
It’s not just flu. Recent studies show vaccines for mumps, pertussis, meningococcal disease, and yellow fever also lose their effectiveness faster than official immunization recommendations suggest. Vaccines have been a crucial public health tool for decades, so it may seem strange that their durability isn’t well understood. But vaccines are approved and come to market years before it’s clear how long protection lasts. Later, fading protection can go unnoticed because a vaccine in wide use has largely eliminated transmission of the microbes it protects against, making “breakthrough” infections rare. Even if viruses or bacteria are still in circulation, people vaccinated against them will sometimes receive natural boosting of their immunity. And declining vaccine immunity is not an all-or-nothing phenomenon: A breakthrough infection often leads to much less severe symptoms of the disease.
Researchers are ramping up efforts to figure out why some vaccines protect for mere weeks but others work for life. “We simply don’t know what the rules are to inducing long-lasting immunity,” says Plotkin, who began to research vaccines in 1957. “For years, we were making vaccines without a really deep knowledge of immunology. Everything of course depends on immunologic memory, and we have not systematically measured it.”
Bali Pulendran, an immunologist at Stanford University in Palo Alto, California, has reached the same frustrating conclusion about vaccine durability. “I keep saying, ‘It’s not well understood, it’s not well understood.’ This is one of the major issues in vaccines.” Deepening the confusion, two essential vaccines, against diphtheria and tetanus, appear to have better durability than widely presumed.
Yet some clues are surfacing from unusually successful vaccines that drive the immune system to mount effective responses for decades, if not an entire human life. One comes from the vaccine against the cancer-causing, sexually transmitted human papillomavirus (HPV), which has proved remarkably durable since it debuted about a decade ago, spotlighting a novel mechanism of long-lasting protection. New insights about durability are also leading researchers to more intensively scrutinize the vaccine booster recommendations by ACIP and similar oversight bodies.
Still, Wayne Koff, an immunologist who heads the nonprofit Human Vaccines Project in New York City, says vaccine durability deserves far more attention than it has received. “If you could understand this,” Koff says, “you could make all vaccines better.”
Mimicking natural immunity
More than 150 years ago, a natural experiment on a rocky, volcanic archipelago between Scandinavia and Iceland proved that an infection can trigger lifelong immunologic memory. Measles raced through residents of the Faroe Islands in 1781. The disease did not reappear on the isolated island group for 65 years, when a visitor brought it back. A thorough study found that no one alive during the first outbreak became ill again. Their elderly immune systems remembered and fought off the virus.
Vaccinemakers aim to duplicate such spectacular feats of immune memory. They create harmless mimics of disease-causing viruses or bacteria, or their toxins, designed to teach immune systems to recognize the real thing and quickly mount robust immune responses. Immunologists believe that for many infectious diseases, long-lived memory B cells are key to that response. When confronted by known enemies, those cells quickly expand and produce hordes of antibodies that latch onto the invaders, preventing infections. Vaccines also can train “killer” T cells, which mop up when antibodies fail, eliminating infected cells.
“For a lot of the things we have vaccines against, antibodies are probably the protective mechanism,” says Mark Slifka, an immunologist who specializes in vaccine studies at the Oregon National Primate Research Center in Beaverton. “For the hard ones to vaccinate against—TB [tuberculosis], malaria, HIV—antibodies play some role, but you need T cells.”
Vaccine designers debate the best way to trigger those responses. Some designers hold fast to the idea that a live but weakened pathogen—or genes from it stitched into a harmless virus that acts as a Trojan horse—induces the longest-lasting, most robust responses. Just such a weakened virus is the basis of the measles vaccine, for example, which protects for life. But Pulendran calls this notion simpleminded. He and others argue that a killed pathogen or a genetically engineered variant of it can work equally well.
For the flu, both killed (also known as inactivated) and live virus vaccines exist—and neither offers sturdy protection. Even when they closely match the circulating strains of influenza viruses, both types protect only about 60% of vaccinated people. And those modest immune responses rapidly wane.
If you could understand [durability], you could make all vaccines better.
In a 2018 review of 11 recent studies on the durability of influenza vaccines, researchers concluded that effectiveness can vanish as soon as 90 days after vaccination. The article, published in Clinical Infectious Diseases, further noted that 20% of Americans received their flu vaccines for a given season by the end of September—which means the vaccine may do nothing come peak flu spread in January and February. “The further away you get from your vaccine, the higher the risk that you’ll contract influenza,” says study co-author Kunal Rambhia, a drug delivery specialist working on a Ph.D. at the University of Michigan in Ann Arbor. “This has huge implications.”
Rambhia says ACIP has good reason to urge people to get vaccinated early, given the challenge of immunizing more than 100 million Americans each year. “They’re making the best decision they can,” he says. “They acknowledge that the vaccine might be less effective toward the end of the flu season.”
He and others also note that a vaccine can offer a benefit even if it “fails.” In people who receive the flu vaccine but become ill, the disease often is markedly less severe. Such partial protection was first recognized more than a century ago with the smallpox vaccine, which fully prevents disease for only a few decades, but powerfully shields people from severe illness and death for life.
Resurgence of mumps
Before the mumps vaccine came to market in 1967, more than 90% of U.S. children suffered from the viral disease, which swells the salivary glands and causes a puffy face and fever. By the 2000s, the country had only a few hundred cases per year. But then in 2006, mumps surged on college campuses in the Midwest, with 6500 cases tallied before the year’s end. Nearly 85% of the college-age people who became ill had received the recommended two doses of the mumps vaccine. Despite wide use of the vaccine, mumps outbreaks continue in the United States on college campuses and in tightly knit religious communities.
Some researchers speculate that the vaccine fails because mutations in the virus allow it to evade the immunity generated by the vaccine. But epidemiologist Joseph Lewnard of the University of California, Berkeley, and immunologist Yonatan Grad of the Harvard T.H. Chan School of Public Health in Boston recently analyzed data on the outbreaks—which have also occurred in Europe, Asia, and Canada. They reported last year in Science Translational Medicine that the disease disproportionately strikes people between 18 and 29. That pattern, Lewnard and Grad conclude, implies the vaccine itself loses effectiveness, because a new mumps strain that has genetically “escaped” should strike other age groups just as often. In a dozen other studies of mumps outbreaks around the world, researchers have also found signs of waning protection.
Lewnard and Grad’s modeling indicates that adding a third dose of mumps vaccine around age 18 and then booster shots every 10 years could dramatically decrease the likelihood of outbreaks. The researchers note that since 1991 the U.S. military has given all its recruits a mumps vaccine booster and not had a single outbreak, even though troops live in close quarters.
Sorting out waning immunity from other factors that influence a vaccine’s success isn’t straightforward, as a mumps outbreak that began in Arkansas in August 2016 shows. More than half the cases were in school-aged children, 92% of whom had been fully vaccinated. “At first, I thought the data had to be wrong because they didn’t fit our model,” Grad says.
The outbreak, which continued until September 2017 and afflicted nearly 3000 people, was concentrated in people from the Marshall Islands. They have a large community in rural Arkansas that attends the same churches and lives in jam-packed houses. According to a February report in The Lancet Infectious Diseases, they have a large community in rural Arkansas that attends the same churches and lives in jam-packed houses. Intense exposure to mumps in the close-knit community apparently overwhelmed what should have been robust protection. “Protection from a vaccine is not all or nothing,” Grad says. “The more exposed you are, the likelier you are to get infected.”
That was a mistake, says Slifka, who, along with his work at the primate lab, is president of NajÃt Technologies, a Beaverton-based company making a new yellow fever vaccine. In the December 2016 issue of the Expert Review of Vaccines, he and his NajÃt colleague Ian Amanna argue that what looked like near-perfect protection to the expert committee reflects the fact that many vaccinated people are never exposed to yellow fever. The authors also point to a Brazilian study that came out after the expert committee’s analysis, which reported 459 cases of the disease in vaccinated people in that country alone over 35 years. In 52% of those cases, 10 years or more had passed since the person’s vaccination. “The yellow fever vaccine–induced immunity is long-lived, but only in 80% of people,” Slifka says.
Antibody data back that argument. Slifka and Amanna point to a Centers for Disease Control and Prevention (CDC) review of nine studies that analyzed blood levels of yellow fever antibodies that can “neutralize” the virus, a test tube measure of potency that is key to a vaccine’s effectiveness. Four of the studies were done in people from areas where yellow fever virus circulates, finding that 97.6% of them had detectable neutralizing antibodies 10 years after vaccination. But in the other five studies, from areas with little or no yellow fever, only 83.7% of vaccinated people had those signs of immunity. To Slifka, that finding indicates that without periodic exposure to the pathogen, people gradually lose protection. “We need at least one booster,” he says.
Plotkin says he strongly agrees that WHO should reconsider its recommendation to drop booster shots. “There’s no doubt there’s a problem,” he says.
A WHO spokesperson for the expert committee that evaluates vaccines says it continues to review new data on breakthrough cases of yellow fever, closely monitoring the duration of immunity in people who received a single dose. “The evidence provided does not support the need for [a] booster dose,” the spokesperson says, noting that WHO cautions against “overinterpretation” of antibody data.
Combo confusion
Some vaccinologists are also questioning a 1991 switch to a putatively safer vaccine against pertussis, which causes whooping cough. For decades, the United States and other countries enjoyed great success with a vaccine made from killed Bordetella pertussis, the bacterium that causes the disease. But that “whole cell” vaccine became the centerpiece of an antivaccine movement some 40 years ago because of a much-debated claim that in rare cases it caused serious neurological damage. So an acellular vaccine, containing an inactivated version of the pertussis toxin that causes the disease as well as pieces of B. pertussis, replaced it.
The vaccine is given with two others, against diphtheria and tetanus. ACIP calls for six doses of the triple-combo vaccine between infancy and age 12. It then recommends tetanus and diphtheria boosters every 10 years for adults. Despite the rigorous vaccination schedule, in 2010–11 and 2014–15 California experienced about 20,000 pertussis cases in two massive outbreaks.
To find out whether waning protection was to blame, Kaiser Permanente in Northern California, a health care system that has detailed medical records for its millions of long-term patients, examined more than 4000 children from 2006 to 2015. The team concluded that protection waned 27% per year after children’s fifth dose of the acellular vaccine, which is given between ages 4 and 6. “We will be increasingly vulnerable to pertussis outbreaks until vaccines which provide more enduring protection are developed,” the researchers concluded in their analysis in the 8 June 2017 issue of Vaccine.
Slifka says the replacement of the whole cellular vaccine with the acellular one was unnecessary and a mistake. “Acellular starts with 80% to 90% protection but crashes over the next few years,” he says, which leaves many children dangerously susceptible between their fifth dose and sixth given at 11 or 12 years of age. (B. pertussis causes relatively mild symptoms, if any, in teens and adults but can be deadly in younger children.)
Ironically, the two other components of the triple vaccine have surprising staying power. The primate center where Slifka works draws blood from its employees to monitor potential infections to and from monkeys and other nonhuman primates. Slifka, Amanna, and colleagues obtained blood samples collected over a 26-year period and assessed how quickly antibodies to the tetanus and diphtheria bacteria decayed after vaccination. It would take more than 40 years for people to begin to lose protective immunity against those two pathogens, they reported last year in PLOS Biology. “We have a much higher level of immunity than previously realized,” Slifka says.
WHO, Slifka notes, already does not recommend tetanus and diphtheria boosters for adults who have received their complete childhood shots. He says ACIP, a rotating group of vaccine experts that meets three times a year and regularly revises recommendations, should also consider withdrawing its recommendation for boosters. He estimates eliminating those shots would save the United States about $1 billion per year.
Just why one vaccine in the trio fades while the others work for almost a lifetime underscores the broader mystery of how to make vaccines more durable. But clues are coming from an unusual vaccine against HPV.
Concerned that an attenuated or an inactivated HPV vaccine might still contain viral components that can cause cancer, researchers genetically engineered another virus to manufacture copies of a harmless HPV surface protein that self-assembles into what’s called a viruslike particle (VLP). Trials have shown that nearly everyone vaccinated with that noninfectious VLP develops high levels of HPV-neutralizing antibodies. Those levels decline moderately after 2 years but then remain stable for at least a decade. “Until we did the human studies with the vaccine, we really weren’t aware we were going to get such consistent and durable antibody responses,” says John Schiller, an oncologist at the National Cancer Institute in Bethesda, Maryland, who in the 1990s pioneered development of the vaccine, which protects against genital cancers and warts.
VLPs challenge the widely held notion that durability depends primarily on memory B cells waking and expanding when an infection occurs. Schiller notes that the HPV vaccine leads to consistent blood levels of neutralizing antibodies for years on end. “If it were memory B cells, you should see spikes, blips up and down,” he says.
Schiller and others contend that VLPs trigger production of a different set of B cells called long-lived plasma cells (LLPCs), which reside in the bone marrow and continually produce antibodies specific to different foreign antigens. “Viruslike particles are clearly the best way to make LLPCs,” Schiller says.
In the wake of the HPV vaccine’s success, VLPs have become a trendy vaccine strategy. A hepatitis E vaccine on the market in China uses VLPs, and experimental influenza, norovirus, chikungunya, encephalitis, malaria, and dengue VLP vaccines are in development.
Yet no one knows precisely how VLPs prod the immune system to make LLPCs. Schiller points to the work of Nobel Prize winner Rolf Zinkernagel of the University of Zurich in Switzerland and his then–graduate student Martin Bachmann. They reported 25 years ago that dense, highly repetitive proteins on the surfaces of viruses trigger the strongest antibody responses. A VLP is just such a structure. In theory, that allows the viral antigens to “cross-link” to many receptors on the surface of B cells. That, in turn, triggers a cascade of signals in immune cells that lead to strong, durable antibodies. How? “That’s the million-dollar question,” Slifka says.
Such unknowns frustrate him, he says. He also laments what he sees as a disconnect between epidemiologists who investigate vaccine breakthrough infections during outbreaks and the type of laboratory studies he and other researchers conduct about immune mechanisms of protection and their durability. “How do we sort out this mess?” he asks. “We need to have the epidemiologists and the immunologists discuss their findings. Both sides could learn so much.”
The flu season in North America is ending. CDC estimates that the virus sickened nearly 40 million people, hospitalized half a million, and killed up to 50,000. Neither Stanley Plotkin nor his wife developed the disease.
Artificial intelligence (AI) is increasingly seen as atool in biopharma and life sciences to improve drug development. There is a bit of a resource lag because AI is expensive. For example, Google/Alphabet owns an AI laboratory called DeepMind. Google acquired DeepMind in 2014 for a reported $650 million.
Google, as one of the biggest corporations on Earth, is very interested in the use of AI and health care.
“The fundamental underlying technologies of machine learning and artificial intelligence are applicable to all manner of tasks,” Greg Corrado, a neuroscientist at Google, told NPR. And that’s true, “whether those are tasks in your daily life, like getting directions or sorting through emailing, or the kinds of tasks that doctors, nurses, clinicians and patients face every day.”
It’s probably not altruism that has brought Google and other tech companies to look at the life sciences and health care. John Moore, an industry analyst at Chilmark Research, told NPR, “It’s pretty hard to ignore a market that represents about 20 percent of [U.S.] GDP. So whether it’s Google or it’s Microsoft or it’s IBM or it’s Apple, everyone is taking a look at what they can do in the health care space.”
Alphabet’s Verily focuses on health. One project the company is working on is software that can diagnose diabetic retinopathy, which can cause blindness. It is being used in India. It is also working to develop contact lenses that can monitor blood sugar in diabetes patients.
Verily’s chief medical and scientific officer, cardiologist Jessica Mega, told NPR, “In each of these cases, you can use new technologies and new tools to solve a problem that’s right in front of you. In the case of surgical robotics, this idea of learning from one surgery to another becomes really important, because we should be constantly getting better.”
Earlier this year, Google’s DeepMind won a worldwide contest called the Critical Assessment of Structure Prediction (CASP), which is hosted by the Protein Structure Prediction Center, which is sponsored by the U.S. National Institute of General Medical Sciences (NIH/NIGMS). It’s a global contest or experiment that has taken place every two years since 1994.
Proteins have three-dimensional structures and those structures are an important element in how they function. For example, it’s common for a mutation in the gene for a protein to result in the protein having a different shape, causing it to behave abnormally or not at all. Proteins shapes are also dynamic, transitioning between different states.
In CASP, the participants attempt to predict the 3-D shape of a specific human protein. Researched who do this type of work use a variety of methods to solve the problem. DeepMind didn’t just beat out the other scientists in the competition but gave a prediction that was almost twice as accurate as experts expected.
Derek Lowe, who writes the In The Pipeline blog for Science Translational Medicine, told The New York Times, “It is not that machines are going to replace chemists. It’s that the chemists who use machines will replace those that don’t.”
Other companies than Google are focused on AI and machine learning. Recursion Pharmaceuticals, headquartered in Salt Lake City, Utah, is a clinical-stage biotech that combines AI, experimental biology and automation to discover and develop drugs at scale.
In January, Recursion announced progress in its collaboration with Takeda Pharmaceutical on identifying novel preclinical candidates for rare diseases. In 18 months, the partnership led to the evaluation of Takeda preclinical and clinical compounds in more than 60 unique indications. New therapeutic candidates were identified in more than six diseases.
San Francisco-based Atomwise uses AI based on convolutional neural networks, the same tech used in facial recognition and self-driving cars, to search for drugs. In January Atomwise signed a strategic alliance with contract research organization (CRO) Charles River Laboratories International, to support CRL’s hit discovery, hit-to-lead, and lead optimization efforts.
And those are just two examples out of many. But Google, as probably the biggest data company in the world and certainly the best known, brings a huge amount of resources to the space. At least part of its focus is directly on patient diagnoses. NPR notes that hospitals have enormous amounts of patient data in electronic health records, scans, test results. “That’s fodder for algorithms to ingest and crunch. And Mega says there’s a potential to wring a lot more useful information out of it.”
Verily partnered with Duke University and Stanford University in what is called Project Baseline. Baseline is looking to recruit 10,000 volunteers to provide additional data to the company. In addition to taking a variety of heart scans, blood tests, stress tests, and skin swabs, participants fill out quarterly questionnaires, a device under the mattress tracks sleep patterns, and they wear heart and exercise monitors.
If this seems to violate your privacy—after all, this is a company that has access to everything you search for and probably buy online, as well as other data—that’s one aspect of the project that might raise concerns. But so far, computer users have been willing to give up a certain amount of privacy for the convenience of what Google offers. That may apply to their health as well.
