Containing Covid requires rapid tests highly sensitive to infections. Why is the FDA asking for something different?

 With rapid testing becoming a key tool in the fight against Covid-19, in a mid-October call with the White House I offered to sell my Covid testing company — recently valued at $99.8 million — to the government for just $1. As an alternative, I also offered to sell the government our test at cost.

My company, Global Diagnostic Systems, had just completed clinical trials showing our rapid Covid-19 home test had 100% sensitivity (meaning no false negatives) and 95% specificity (meaning just 5% false positives). On hearing about this performance, a senior White House official told me, “Apply to the FDA ASAP.”

At a cost of about $2 a test, the government could make 166 million tests for the same $232 million it paid in May to buy 8.5 million tests from an Australian company that had already received $30 million in U.S. government funds from the National Institute of Health’s Rapid Acceleration of Diagnostics (RADx) initiative to develop its rapid Covid antigen test, which retails for $40.

But after my call with the White House, the Food and Drug Administration instituted ill-considered guidelines that make our test — and other similarly solid tests — “unacceptable” for authorization. The new FDA guidelines now say that rapid Covid home tests should have at least 98% specificity (2% false positives), but can have as low as 80% sensitivity (20% false negatives). That’s consistent with tests currently on the market, most of which have high specificity but sensitivity in the mid-80% to low-90% range.

That’s the wrong way to go.

A key to containing the impact of Covid-19 is early detection and early treatment. That calls for highly sensitive tests, so positive cases aren’t missed. Everyone who takes a rapid Covid-19 test before getting together with others — whether in an office, at home, or on a football field — wants to be as confident as possible that a negative result is a true negative. Those who are at high risk of severe consequences if they become infected, such as the elderly and those who are immune compromised, are particularly concerned with the accuracy of negative test results. They should be able to choose a test that is extremely sensitive, which reduces the chance of a false negative.

Yet the FDA is doing the opposite — encouraging tests with low sensitivity — which will often falsely tell people infected with SARS-CoV-2, the virus that causes Covid-19, they are negative. It’s unwise.

For example, a test made by OraSure, which received $327 million in government funding to develop it, has 98% specificity and 84% sensitivity. Abbott’s BinaxNOW, the most popular rapid test, has 98.5% specificity and 84.6% sensitivity, though a CDC study found just 64.2% sensitivity.

It should be easy to see the value of distributing billions of highly sensitive Covid tests to a nation of nearly 330 million people who need to routinely test themselves for Covid-19. A negative result can give reassurance. Those who test positive can isolate themselves to prevent spreading infection and, if needed, get early treatment.

An airborne virus knows no boundaries. Today’s Covid-19 outbreak in South Africa leads to next month’s infection in the south of France and South Carolina. To quell the pandemic, the government should initiate and lead a consortium funded by multiple nations to distribute Covid-19 tests, treatments, and vaccines around the world. Such a program not only makes sense for humanitarian reasons — like PEPFAR for HIV/AIDS — it’s also in the U.S.’s enlightened self-interest.

The pandemic has already seen successful partnerships between small companies and large ones, like BioNTech and Pfizer in vaccines and Ridgeback and Merck in treatments. Given the pressing need for Covid-19 tests, an entity created out of a partnership between a testing company — mine, or any one of several others — and the government makes sense. The government can invoke the Defense Production Act to speed production of low-cost tests, even using manufacturing facilities it has already funded for much more expensive tests, to quickly make and distribute tests. The realities of this virus, which mutates and evolves, demands that test performance be continually evaluated. For future outbreaks, an organization would be in place to efficiently and effectively develop, make, and distribute low-cost tests.

I formed Global Diagnostic Systems in 2020 with an investment from the Sergey Brin Family Foundation. We had one key goal: to develop a sensitive, easy to use, affordable home test for Covid-19. Development was guided by a key tenet of epidemic control: the need to detect infection early so people can isolate to prevent infecting others and get treatment if needed. So we designed the test to be highly sensitive to limit the number of false negatives.

After a year of hard work and achieving our goal, why would we give the company away? With billions of people on the planet needing tests, it’s essential that rapid Covid-19 tests be inexpensive, easy to use, and highly sensitive. But only the U.S. government has the resources and credibility to harness the production resources to make and distribute billions of tests each month to Americans and others around the world. To help save lives, we felt it was a privilege and honor to offer our company to the government.

As I write this, 1,300 Americans are dying every day from Covid-19. Rapid, highly sensitive tests can help save lives. The FDA needs to revise its guidelines for authorizing rapid tests and the Biden administration needs to employ smart strategy, powerful weapons, and decisive leadership to win this war. The offer to sell the government our company for $1 still stands.

Elliott J. Millenson is the CEO of Global Diagnostic Systems. He was the CEO of Direct Access Diagnostics, which developed the first FDA-approved home HIV test.

https://www.statnews.com/2022/01/06/make-home-covid-19-tests-highly-sensitive-to-infection/

Genprex Expands Gene Therapy Oncology Pipeline to Include Small Cell Lung Cancer

 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, today announced that it has expanded its oncology research and development pipeline to include small cell lung cancer (SCLC) as an additional disease indication for its lead drug candidate, REQORSA™ Immunogene Therapy. SCLC represents approximately 10-15 percent of the lung cancer market, while REQORSA’s initial target indication of non-small cell lung cancer (NSCLC) represents approximately 84 percent of the lung cancer market.

https://finance.yahoo.com/news/genprex-expands-gene-therapy-oncology-130000367.html

Postal Service seeks 120-day waiver from vaccine mandate

 The U.S. Postal Service is seeking a 120-day waiver from the Biden administration’s COVID-19 vaccine mandate, The Washington Post reported. 

In a letter sent on Tuesday to the Occupational Safety and Health Administration (OSHA), Deputy Postmaster General Douglas Tulino wrote that a vaccine mandate and weekly COVID-19 testing for employees would hurt the agency’s ability to deliver mail to residents and strain the supply chains. 

The Postal Service also asked OSHA to extend its compliance deadlines for 120 days and suspend the agency's obligations under the required mandate until the courts make a final decision on the matter, according to the Post. 

The latest vaccine mandate takes effect on Jan.10, but OSHA won’t issue any citations until Feb.9. 

“We respectfully suggest that the nation cannot afford the additional potential substantial harm that would be engendered if the ability of the Postal Service to deliver mail and packages is significantly negatively impacted,” Tulino said in his letter.

Tulino also wrote in his letter that the agency has taken more steps to prepare its human resources software system to manage worker health data. 

He added that discussions have started with labor unions about the impending mandate and that the Postal Service had begun revising its COVID-19 vaccination, testing and face-covering policy, the Post reported. 

The U.S. is currently dealing with a winter surge of COVID-19 infections as the omicron variant takes hold.

In a statement, a Postal Service spokeswoman, Darlene Casey, said the agency will continue to enforce its existing coronavirus mitigation program, the Post noted. 

“The Postal Service is seeking temporary relief because it wants to ensure that its ability to deliver mail and packages is not hindered amid the current disruptions in the nation’s supply chain,” Casey told the Post.“In addition, the Postal Service wants to adopt policies and procedures that comply with the [OSHA standard] while also fulfilling the organization’s other legal obligations.”

https://thehill.com/policy/healthcare/588494-postal-service-seeks-120-day-waiver-from-vaccine-mandate

With sexually transmitted infections off the charts, California pushes at-home tests

 California has become the first state to require health insurance plans to cover at-home tests for sexually transmitted infections such as HIV, chlamydia and syphilis—which could help quell the STI epidemic that has raged nearly unchecked as public health departments have focused on COVID-19.

The rule, part of a broader law addressing the STI epidemic, took effect Jan. 1 for people with state-regulated private insurance plans and will kick in sometime later for the millions of low-income Californians enrolled in the state’s Medicaid program.

By making it easier and cheaper for Californians to self-administer tests in the privacy of their homes, the provision could bring better disease monitoring to rural and underserved parts of the state, reduce the stigma patients experience when seeking care and give them more control over their health, say experts on infectious diseases.

“This is the first law of its kind, and I’d say it’s kind of cutting-edge,” said Stephanie Arnold Pang, senior director of policy and government relations for the National Coalition of STD Directors. “We want to bring down every single barrier for someone to get STI testing, and out-of-pocket cost is a huge factor.”

But being first has its downsides. Because the concept of insurance coverage for home STI tests is so new, the state’s Medicaid program, Medi-Cal, could not establish by Jan. 1 the billing codes it needs to start paying for tests. Federal regulators also haven’t approved the tests for home use, which could make labs reluctant to process them. And a state analysis predicts most in-network healthcare providers won’t start prescribing home tests for at least a year until they adjust their billing and other practices.

Nevertheless, the situation is urgent and requires action, said state Sen. Richard Pan, D-Sacramento, a pediatrician who wrote the law.

“We have children born in California with syphilis,” Pan said. “You’d think that went away in the Victorian era.”

Even before COVID, sexually transmitted infections hit all-time highs in the U.S. and California (PDF) for six years in a row, according to 2019 data from the Centers for Disease Control and Prevention. Rates of congenital syphilis, which babies contract from their mothers, illustrate the severity of the STI epidemic: Cases were up 279% from 2015 to 2019 nationally and 232% in California. Of the 445 cases of congenital syphilis in California in 2019, 37 were stillbirths.

The pandemic only worsened the problem because health departments were overwhelmed responding to the COVID emergency, and stay-at-home orders kept people away from clinics.

In surveys of public health programs across the country since May 2020, the National Coalition of STD Directors found that most respondents—up to 78% in one survey (PDF)—have diverted some of their STI workforces to test and monitor COVID. A report that accompanied the most recent survey found that some STIs were “completely unchecked” due to reductions in clinic hours, diversion of resources, shortages of testing kits and staff burnout.

Some at-home STI tests screen for a single disease but other kits can collect and send samples to check for a variety of infections. Depending on the test, patients collect a drop of blood with a lancet, or swab their mouth, vagina, anus or penis.

Some tests require patients to send samples to a lab for analysis, while some oral HIV tests give results at home in a few minutes.

Ivan Beas, a 25-year-old graduate student at UCLA, was getting tested frequently as part of a two-year research study. When clinics closed during the pandemic, researchers sent him a home kit.

The kit, which tests for HIV, hepatitis C, herpes, syphilis, chlamydia, gonorrhea and trichomoniasis, was packaged discreetly and came with easy instructions. It took Beas about 10 minutes to prick his finger, swab his mouth and send the samples to the lab.

Beas wanted to continue screening himself every few months after the study ended, he said, but the kit he used retails for $289, which is out of reach for him.

The last time he went to a clinic in person, “I spent two hours waiting to even be seen by a doctor because of how busy they are,” he said. Until Medi-Cal begins covering home tests, he said, he will have to find time to get tested for free at a Planned Parenthood clinic.

“If insurance were to cover it, I’d definitely do it more,” he said.

Under California’s new law, plans regulated by the state must cover home STI tests when ordered by a healthcare provider.  

Privately insured Californians can take advantage of the coverage immediately. How much they will owe out-of-pocket for the tests—if anything—depends on the type of plan they have, whether their provider is in-network, and if they fall into a category the federal government has designated for free screening.

Medi-Cal patients almost never face out-of-pocket expenses, but they will have to wait for coverage because the Department of Health Care Services, which administers Medi-Cal, is working with the American Medical Association and the federal government to create billing codes. The reimbursement rates for those codes will then need federal approval.

The state doesn’t know how long that process will take, according to department spokesperson Anthony Cava.

The rule does not apply to the millions of Californians whose job-based health insurance plans are regulated by the federal government.

Other states and organizations have experimented with at-home STI tests. The public health departments in Alabama and the District of Columbia send free kits to residents who request them, but neither jurisdiction requires insurance coverage for them. The National Coalition of STD Directors is sending free kits to people through health departments in Philadelphia; Iowa; Virginia; Indiana; Puerto Rico; and Navajo County, Arizona. The list of recipients is expected to grow this month.

Iwantthekit.org, a project of Johns Hopkins University, has been sending free kits to Maryland residents since 2004, and to Alaskans since 2011. The program is funded by grants and works with local health departments.

Charlotte Gaydos, co-founder of the project, said that requests for test kits during the pandemic nearly tripled—and that she would expand to every state if she could bill insurance the way the California law mandates.

The tests fall into a murky regulatory area. While they have been approved by the Food and Drug Administration, none have been cleared for use at home. Patients are supposed to collect their own samples within the walls of a health facility, and some labs may not analyze samples collected at home.

Public health officials cited other potential challenges: Patients may not have the same access to counseling, treatment or referrals to other services such as food banks that they would receive at clinics. And although patients are supposed to self-report the results of their tests to public health authorities, some people won’t follow through.

Vlad Carrillo, 31, experienced such trade-offs recently. Carrillo used to get tested at a San Francisco clinic, where they could get counseling and other services. But Carrillo lost their apartment during the pandemic and moved about seven hours away to Bishop, the only incorporated city in rural Inyo County.

“Being away from the city, it took me a whole year to find a way to get tested,” Carrillo said.

Carrillo eventually got the kit through the mail, avoiding the stigma of going to the clinic in Bishop, which is “more focused on straight stuff,” like preventing pregnancy. Without the test, Carrillo couldn’t get PrEP, a medication to prevent HIV.

“Going without it for so long was really hard on me,” Carrillo said.

https://www.fiercebiotech.com/medtech/sexually-transmitted-infections-off-charts-california-pushes-at-home-tests

FDA, working through pandemic backlog, pauses US factory inspections on omicron concerns

 Just as the U.S. hoped to turn the page on COVID-19, the omicron variant touched down, sending case counts to record levels and reigniting debate over social distancing measures. The FDA, which has accrued a hefty backlog of manufacturing inspections over the past two years, isn’t immune to the latest variant concerns, either. 

Now, shortly after the FDA said it was getting a handle on pandemic-era oversight at home, omicron has forced the agency to pause its work yet again. 

The FDA has put certain inspection operations on hold through Jan. 19 as it works “to ensure the safety of its employees and those of the firms it regulates” in the face of omicron. The pause began last Wednesday, shortly before the New Year, and will last for at least two more weeks, the regulator said Tuesday. Over that stretch, the FDA plans to continue work deemed “mission-critical,” with the goal to restart paused inspections “as soon as possible.” 

The FDA will strive to continue foreign mission-critical inspections, too, though the latest pause has put a damper on plans to overhaul its larger oversight mission abroad—an effort that was scheduled to kick off in February. Now, the agency says it will have to postpone planning for foreign surveillance inspection assignments.

Meanwhile, as it has throughout the pandemic, the FDA says it’s “leveraging other remote tools to maintain oversight of foods, drugs, medical products and tobacco.”

After pausing inspection work in early 2020, the FDA largely returned to “standard operations for domestic inspections” in July 2021, then-acting FDA commissioner Janet Woodcock said that month. By November, the regulator said it had wrapped up 1,139 domestic inspections out of 3,229 outstanding for medical products and devices.

In doing so, the FDA exceeded its goal for U.S. inspections that it laid out in its May 2021 “roadmap” for inspectional resiliency, Judy McMeekin, associate commissioner for regulatory affairs at the FDA, said in a recent interview.

Prior to the latest pause, it seemed possible that the FDA could complete its backlog of domestic drug plant inspections in 2022. That said, the problems facing the FDA abroad run deeper than COVID-19 and are unlikely to be resolved before the year is out, Mary Denigan-Macauley, director of healthcare at the Government Accountability Office (GAO), recently told Fierce Pharma.

Overseas staffing vacancies and language barriers pose two big problems for foreign inspections, Denigan-Macauley explained. The FDA’s McMeekin said the regulator is “actively working on these issues,” pointing to a pilot program the FDA planned to debut in 2022 that would endeavor to “enhance translator capabilities of foreign drug inspections.”

McMeekin also addressed staffing concerns, noting that the agency is actively hunting for “foreign cadre staff”—agency officials who would be based in the U.S. but travel to foreign countries to conduct inspections.

Between April and September of 2021, the regulator carried out just 37 foreign drug inspections, three foreign animal drug inspections, four foreign medical device inspections and two foreign biologics inspections.

Meanwhile, in its mid-November oversight update, the FDA reported 52 new drug application delays because of the agency’s pandemic-related inspection backlog, up from 48 delayed applications reported in May.

The omicron-prompted pause doesn’t come as a “huge surprise given the significant increase in cases globally,” Wells Fargo analysts wrote in a note to clients Wednesday. It does, however, pose a “potential problem to timing for certain approvals (and/or re-submissions) for a number of therapeutic companies,” the team said.

Much of the concern around the FDA's backlog has focused on delays in new drug approvals, but it also presents a problem for companies that have received write-ups from the regulator. Those firms depend on FDA inspections to clear warning letters or import alerts. 

As for alternative oversight tools, the agency has relied upon remote inspections to supplement its work, but remote reviews don’t satisfy the in-person requirements for surveillance inspections. By turning to digital, the FDA could make a dent in the number of user fee delays it clears, but it will still be saddled with hundreds of surveillance inspections that require an in-person touch. 

"We learned through our own experiences thus far and in discussing remote assessment approaches with our foreign counterparts, that remote assessments have presented meaningful technical challenges and require more resources than anticipated," FDA's McMeekin noted.

https://www.fiercepharma.com/pharma/fda-working-through-pandemic-backlog-pauses-us-drug-inspections-omicron-concerns

Berkeley Lights Preliminary Full Year 2021 Financial Update

 Berkeley Lights, Inc., (Nasdaq: BLI), (“BLI” or “the Company”), a leader in digital cell biology, today announced that Eric D. Hobbs, Ph.D. will transition from his role as chief executive officer (CEO) and member of the board of directors to president of the Antibody Therapeutics business line. The Company is initiating a search for a new CEO as it continues to execute on its business strategy, including the successful addition of services to its portfolio of product offerings. Dr. Hobbs will continue to serve in his role as CEO and member of the board of directors until the appointment of his successor.

Dr. Hobbs joined the Company in 2013 to lead the commercial development of Berkeley Lights’ opto-fluidic technology, which resulted in the Beacon system that is broadly recognized as the leading platform for functional characterization of live single cells, and became CEO in 2017. In his new role as president, Antibody Therapeutics, Eric will focus on growing the Company’s largest business line. His deep knowledge of this area, including Berkeley Lights’ technology, customers and future R&D roadmap, will help ensure successful business continuity.

“Under Eric’s leadership as CEO, Berkeley Lights has realized a more than a 10-fold revenue increase, released multiple transformational products, and completed a successful IPO in 2020,” said Gregory T. Lucier, chairperson of Berkeley Lights’ board of directors. “As Berkeley Lights moves into a new chapter of growth, we are grateful we will continue to benefit from Eric’s leadership, talent and insight as we revolutionize how scientists can access primary cell biology to make extraordinary discoveries.”

During 2021, the Company began to enter new markets through a partnership/service-based business model, leveraging the Berkeley Lights Platform through its BioFoundry lab. Revenue from the partnership/service business grew three-fold in 2021 and drove approximately 20% of the Company’s overall 2021 revenue.

Mr. Lucier continued, “As we continue to evolve our business and executive leadership, I will take a more engaged role in providing guidance and support to the management team to advance the collective goal of driving value for our customers, partners and shareholders. We are committed to conducting a thorough CEO search with a focus on identifying a new leader with a proven record of scaling operations and unlocking the potential of highly innovative companies. I remain confident and excited about the opportunities ahead for Berkeley Lights as demand for our innovative technology grows.”

"I am deeply proud of what the Berkeley Lights team has accomplished. We are at a critical transition point in the Company’s history and it’s time for a new leader to help build upon our successes,” said Dr. Hobbs. “Berkeley Lights is well positioned to advance its leadership in the digital cell biology market over the next decade as our technology proves ever more critical to the most exciting scientific advances.”

Mr. Lucier is a long-tenured life sciences executive, having served as chairman and CEO of Life Technologies, which was acquired by Thermo Fisher Scientific in 2014, as well as CEO and a member of the boards of directors of several public and private companies.

The board of directors has engaged Russell Reynolds Associates, an executive search consultant, to assist in its comprehensive external CEO search process.

Full Year 2021 Financial Update

The Company also reported preliminary, unaudited revenue for the full year ended December 31, 2021.

Total revenue for the full year 2021 is expected to be in the range of $84.0 million to $84.5 million, representing an increase of more than 30% compared to $64.3 million in 2020.

In 2021, the Company signed new contracts with total revenue value of up to $115 million, inclusive of direct sales and approximately $42 million in partnership/services business, demonstrating the continued adoption of Berkeley Lights technology. In addition, recurring revenue grew more than 35% compared to prior year.

These preliminary results are based on management’s initial analysis of operations for the quarter ended December 31, 2021. The company expects to issue full financial results for the fourth quarter and full year 2021 in late February.

2022 Outlook

The Company expects revenue for 2022 to grow approximately 30% compared to prior year revenue. Partnership/services business revenue is expected to continue to grow, both in absolute dollars and as a percentage of total revenue, and anticipate this to fuel total company growth in 2023 and beyond. Further details will be discussed on the fourth quarter and full year 2021 earnings call.

J.P. Morgan Healthcare Conference Participation

Berkeley Lights management is participating virtually in the upcoming 40th Annual J.P. Morgan Healthcare Conference on Tuesday, January 11 at 12:45 p.m. Pacific Time / 3:45 p.m. Eastern Time. Interested parties may access a live and archived webcast of the presentation on the “Investors” section of the company website at www.berkeleylights.com.

https://finance.yahoo.com/news/berkeley-lights-announces-ceo-transition-210200043.html

Sutro’s folate challenge to Immunogen hits a problem

 When does disclosure of a best-in-class drug profile warrant a share selloff? When it is accompanied by questions about the way data were generated, apparently, along with concerns about lack of a therapeutic window.

A case in point is Sutro, which yesterday released an update from an ovarian cancer trial of its folate receptor α antibody-drug conjugate STRO-002. This caused Wells Fargo to trumpet STRO-002’s profile as “best-in-class” – the project is a challenger to Immunogen’s similarly acting mirvetuximab soravtansine, which recently scored in a similar setting – but today Sutro stock opened off 25%.

On the face of it the Sutro update was upbeat: in a pretreated ovarian cancer population not enriched for FRα expression there was a 33% overall response rate to STRO-002, comprising 19% in a 4.3mg/kg cohort and 47% in 5.2mg/kg. Immunogen’s Soraya trial had shown 32% of relapsed ovarian cancer patients responding to mirvetuximab, but this was a FRα-high population.

A cross-trial comparison gives Sutro the efficacy edge, therefore, notwithstanding some subtle differences; 63% and 65% of the patients given STRO-002 had relapsed on Avastin and a Parp inhibitor respectively, versus 100% and 48% in Soraya, for instance. Sutro said ORR was 40% for >25% FRα expressers, and 13% for those at or below the 25% threshold, but even targeting only the former would give STRO-002 70% of the population.

What’s the dose?

Toxicity is a concern, however. Neutropenia is a major problem, with 60% of patients experiencing it at grade 3 or above, and there was one death from febrile neutropenia, in a patient on 5.2mg/kg of STRO-002.

Sutro said a protocol amendment had been implemented to require any 5.2mg/kg patient experiencing grade 4 neutropenia to have their dose cut to 4.3mg/kg. Crucially, however, 5.2mg/kg is the group’s “go-forward” dose for a pivotal study, based on the dose response it claims to have demonstrated.

The key question, therefore, is whether a therapeutic window exists for STRO-002; Sutro claims that responses on 5.2mg/kg are maintained even if the dose is subsequently reduced.

And is there even a dose response? Sutro’s data show some inconsistency as to when they were generated: at the stated November 8 cutoff of the substantive dataset there were three and four confirmed remissions in the 4.3mg/kg and 5.2mg/kg cohorts, respectively.

It is only after post-cutoff follow-up of five additional unconfirmed responses said to be “of interest” that a more convincing dose response emerged: one 4.3mg/kg remission was actually deemed a stable disease, but all four 5.2mg/kg responses were confirmed as real PRs.

Source: Sutro presentation.

Such details aside, it is clear that lack of safety is now the biggest concern surrounding STRO-002.

Not that mirvetuximab has a clean profile itself, of course: in Soraya blurred vision was a common adverse event, and treatment-related AEs led to dose reductions in 19% of patients, dose delays in 32%, and discontinuations in 7%. Immunogen plans to file this quarter, but investors will recall mirvetuximab's 2019 failure in an all-comers population.

Bullish Wells Fargo analysts glossed over STRO-002’s safety profile, while those at Berenberg called its side effects manageable but stopped short of the best-in-class assessment, merely calling the Sutro project competitive against mirvetuximab.

Wells Fargo could still be right. STRO-002 could be the best in a class where toxicity scuppers both assets.

https://www.evaluate.com/vantage/articles/news/trial-results/sutros-folate-challenge-immunogen-hits-problem