Ken reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and provided and managed pharmacy care and drug information services. He regularly contributes to Contagion Live, HCP Live, Neurology Live, and Pain Medicine News.

Kenneth Bender, PharmD, MA

Repeating a booster dose increased the immune response to COVID-19 vaccine in kidney transplant recipients as well or better than repeating the primary 2-dose regimen or interrupting their immunosuppressant with the booster in a trial that investigators report is the first to compare alternative strategies to improving vaccine response in this population.

"...even after a third or fourth vaccination, a considerable proportion of organ transplant recipients remains a serological non-responder. It is therefore imperative to investigate whether alternative vaccination strategies could be more immunogenic," explained Luuk Hilbrands, PhD, Department of Nephrology, University of Amsterdam, Amsterdam, Netherlands, and colleagues.

The investigators enrolled study participants from among kidney transplant recipients (KTR) in the Netherlands who did not have serologic response 14-56 days after a 2-dose primary vaccination or 3rd-dose booster with the mRNA-1273 (Moderna) vaccine. Serologic response was measured by anti-SARS-CoV-2 RBD IgG ELISA assay, with cutoff level for seropositivity of ≥50 binding antibodies units (BAU)/ml.

Participants were randomized to receive either another 2-dose vaccination with mRNA-1273 (n=77); a different vaccine, Ad26.COV2.S (Janssen) (n=78); or to a control group receiving a single booster dose of mRNA-1273 (n=75). In addition, two groups receiving the booster dose either maintained their mycophenolate mofetil- mycophenolic acid (MMF-MFA) (n=53) or discontinued it 1 week before through 1 week after the vaccination (n=52).

Hilbrands and colleagues had noted a strong negative association between MMF-MFA and vaccine immunogenicity, and so sought to determine whether discontinuation might improve immune response. All those who agreed to be randomized to maintain or discontinue MMF-MFA were receiving triple immuosuppressive therapy consisting of a calcineurin inhibitor, MMF or MFA, and steroids.

"Reduction of immunosuppression in patients using dual therapy was not deemed feasible," Hilbrands commented to 

"Another (untested) strategy could be to replace MMF by another immunosuppressant, (such as) azathioprine or an mTOR inhibitor," he opined.

An additional condition that is yet to be tested is withholding of MMF-MFA at the time of the full, 2 dose primary vaccination."The reason to withhold MMF during 2 weeks (in the trial) is the observation that in the basic vaccination schedule, patients using MMF were low responders. So, at the time of basic vaccination schedule, this information was not available," Hilbrands pointed out.

The investigators reported that vaccination with the 2-dose mRNA-1273 or Ad26.COV2-S were not superior to single dose mRNA-1273; with seroresponse rates of 68%, 63% and 68%, respectively. The holding of MMF-MFA was also not statistically significantly superior to maintaining the immunosuppressant; with seroresponse rates of 80% and 67%, respectively.

Hilbrands and colleagues concluded that repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs without additional effect fromhigher doses, a heterologous vaccine, or 2 weeks discontinuation of MMF-MFA. They cite other studies demonstrating increased seroresponsive rates after each additional booster vaccination; and advise repeating booster vaccination to achieve stronger response.

"We think that our results are directly useful for doctors caring not only for kidney transplant recipients, but also for other patients on immunosuppresive drugs," they indicate.

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Alternative strategies to increase immunogenicity of COVID-19 vaccines in immunosuppressed kidney transplant recipients are evaluated in clinical trial.

Trial Tests Methods to Increase COVID-19 Vaccine Response in Kidney Transplant Recipients


An early season surge of RSV and other respiratory illnesses requiring children to be hospitalized at historically high rates has been attributed, in part, to the withdrawal of precautions against COVID-19 which had reduced exposure to, as well as immune recognition of other respiratory viruses.

The circumstance is described in an analysis in 

 as an "immunity debt," incurred during the period of protective measures such as masking and social distancing which had protected many children.

"But this year, as in-person gatherings and travel increased and kids went back to school and daycare without masks, the virus has ripped through a large pediatric population with little to no immunity," the analysis recounts.

 of this pattern across the globe, Thomas Williams, MB BChir, MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK, and colleagues assert that the timing of such a "delayed" peak could be anticipated.

"For countries that have experienced an entire year without RSV or influenza, mathematical modeling suggests the possibility of a hard rebound marked by increased morbidity and mortality from one or both viruses in the winter of 2021/22," Williams and colleagues wrote in an article published last July.

Although possibly foreseeable, the magnitude and severity of the surge has quickly challenged the capacity of children's hospitals and pediatric offices in the US.

 to President Biden and Xavier Becerra, Secretary of the Department of Health and Human Services, sent jointly from the executive officers of the Children's Hospital Association and the American Academy of Pediatrics, called for declarations of both a national emergency and a public health emergency.

"The pediatric health care system is doing all it can to meet these overwhelming needs across the continuum of care and taking regional approaches to meet the growing demands. We need emergency funding support and flexibilities along the same lines of what was provided to respond to COVID surges," wrote Mark Wietecha, CEO, Children's Hospital Association, and Mark Del Monte, JD, CEO/executive vice president, American Academy of Pediatrics (AAP).

Declaring both types of emergencies would, according to Wietecha and Del Monte, allow waiver of certain requirements of the Medicare, Medicaid, or Children's Health Insurance Program (CHIP), and of the Emergency Medical Treatment and Labor Act, which could facilitate sharing of resources. Among the anticipated measures would be increased transferring of patients and creating off-site triage to manage capacity challenges; and licensure reciprocity to support cross state care and telehealth.

In their letter, Wietecha and Del Monte relate that more than three-quarters of pediatric hospital beds are full, and that many states are reporting that 90 percent of their pediatric beds are occupied. They point to ongoing attempts to care for this population in community care centers and at adult hospitals, which have limited or no capacity to care for children.

 corresponding to the joint letter, Wietecha warned, "Our system is stretched to its limit and without immediate attention the crisis will only worsen."

 on November 4, José Romero, MD, Assistant Secretary for Preparedness and Response, commented that vaccination is the best defense in preventing influenza and COVID-19. While 

, non-pharmaceutical measures remain important for reducing exposure to, and transmission of these respiratory viruses.

"People should also practice everyday preventive measures such as cough hygiene, or etiquette that is covering your coughs and sneezes, staying away from individuals who are ill, and frequent hand washing or using alcohol gels," Romero encouraged. "People may also choose to wear a well-fitting mask as an added precaution."

Earlier and higher rates of RSV and other respiratory illnesses following reduced COVID precautions challenge capacity of pediatric units.

RSV Resurges as COVID Pandemic Precautions Recede


Increased research and development of antifungals and improved public health policies to address the threat of invasive fungal diseases (IFDs) are proposed in the recently released WHO Fungal Priority Pathogens List (

"Countries are encouraged to follow a stepwise approach, starting with strengthening their fungal disease laboratory and surveillance capacities, and ensuring equitable access to existing quality therapeutics and diagnostics, globally," urged Haileyesus Getahun, MD, MPH, PhD, WHO Director, Antimicrobial Resistance(AMR) Global Coordination Division, in an accompanying 

Getahun and colleagues of the AMR Division developed the document to aid in addressing multiple challenges, including the toxicity and expense of existing antifungal medicines, and that particular expertise is required to administer them effectively and with consideration of common drug-drug interactions.

"Additionally, affordable access to quality medicines and diagnostic tests is unevenly distributed. This is especially acute in low-resource settings, where the disease burden is highest," Getahun and colleagues indicate. "As a result, many fungal infections go undiagnosed and untreated. Causative pathogens are rarely confirmed microbiologically, and in most settings, surveillance data are of low quality or absent."

Their first recommendation is to utilize the FPPL ("as the first global effort to systematically prioritize fungal pathogens") to focus action on the prioritized targets. The document then identifies 3 broad areas for action: improved surveillance, targeted support for R&D and innovation, and enhanced public health interventions.

State-of-Art surveillance testing tools, such as MALDI-TOF (matrix-assisted laser desorption/ionization time of flight) mass spectrometry systems and real-time PCR, as well as antifungal therapeutic monitoring are recognized as currently too costly for other than high-income settings. The FPPL urges increased access, however, to mycology laboratories employing microscopy and cultures; and to such diagnostic tools as CT and MRI imaging, and advanced sampling by bronchoscopy and CT-guided biopsy.

Large-scale susceptibility data collection with clinical data linkage is considered key to developing clinical breakpoints for the target pathogens.The document calls for increased collaborative use of national and international level surveillance programs like the WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS)—which, in 2019, expanded its original scope from bacterial infections to include fungi.

for fungal infections is estimated in the FPPL to receive 1.5% of all infectious disease research funding. The consequence, it indicates, is a weak evidence base with most treatment guidelines informed by limited evidence and expert opinion.

"Tackling the problems posed by IFD will require increased research funding, targeted at the key priorities, new antifungal medicines and improved diagnostics," Getahun and colleagues indicate.

Focus on innovative antifungal agents in new chemical classes and new modes of actions—without cross-resistance to other antimicrobial classes and minimal drug-drug interaction

Improve existing therapies by characterizing optimal use, including determining pharmacokinetics/pharmacodynamics and therapeutic antifungal monitoring

Develop rapid diagnostic and point-of-care tests for priority pathogens

Improve efficacy, efficiency and quality of fungal identification and susceptibility testing

Getahun and colleagues argue that public health

interventions must be built on the foundation of surveillance and R&D, along the identified priorities. "A deep, granular understanding of the dynamics of disease burden—incidence, prevalence, mortality and morbidity—and the prevalence of AMR for these priority pathogens will facilitate rational interventions," they indicate.

They recognize, however, that health workers in many regions are unfamiliar with fungal infections; with the resulting low clinical suspicion, misdiagnosis, incorrect or delayed treatment, and poor patient outcomes.

"To address this, fungal infections need to be mainstreamed beyond specialized training programs as part of early and ongoing medical and public health training," Getahun and colleagues recommend.

The World Health Organization (WHO) describes measures necessary to confront invasive fungal infections from the pathogens posing highest threat and greatest disease burden.

WHO Identifies Actions to Address Invasive Fungal Infections

A recently issued call and guide for global action against the public health threat of invasive fungal diseases (IFDs) by the World Health Organization (WHO) ranks the risks posed by 19 pathogens, including 4 deemed "critical."

"Emerging from the shadows of the bacterial antimicrobial resistance pandemic, fungal infections are growing, and are ever more resistant to treatments, becoming a public health concern wordwide," said Hanan Balkhy, MD, Assistant Director-General, Animicrobial Resistance (AMR), WHO, in an accompanying 

WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action

 (WHO FPPL)was developed by members of the multinational AMR Division, overseen by Haileyesus Getahun, MD, MPH, PhD, WHO Director, Antimicrobial Resistance(AMR) Global Coordination Division.

Getahun and colleagues point out that the rise in IFDs are particularly notable among immunocompromised populations; and that diagnosis and treatment are challenged by limited access to quality diagnostics and treatment, and to the emergence of antifungal resistance.

 article citing the WHO document highlights its assessment that the present antifungal armamentarium is too limited and too toxic; with the last new class (of only 4 total) to treat severe infection approved over two decades ago. The article notes, however, the hopeful progress with fosmanogepix (Amplyx Pharmaceuticals), rezafungin (Cidara Therapeutics), olorofim (F2G Ltd); and a potentially less toxic version of amphotericin B (Matinas BioPharma).

The 4 pathogens deemed "critical" targets for improved treatments and public policy are:

The next highest priority group includes: 


The document indicates that strong determinants of priority level were from responses to Best-Worst Scaling (BWS) global surveys regarding public health importance and unmet research and development need. Specifically, prioritizing followed from prevalence of antifungal resistance, and disease-burden related criteria (eg, mortality, annual incidence and morbidity).

"The list is focused on fungal pathogens responsible for acute, subacute systemic fungal infections for which drug resistance or other treatability and management challenges exist," Getahun and colleagues explain. "The pathogens included are all associated with serious risk of mortality and/or morbidity."

The ranking involved a weighing of factors, which were illustrated with 2 examples. 

was ranked high for the need for research and development of effective treatment options, but low in perceived public health importance due to its rarity, ranking 13th of the 19. In contrast, while 

 ranked lower for unmet R&D need, they were high for public health burden, resulting in their placement in the highest "critical" group of 4 pathogens.

The document points out that some threatening pathogens are specific to particular geographical areas and populations, and do not now pose risk on a global scale. It advises then, that regions and countries contextualize the findings to inform local actions; and to protect at-risk populations (

, cancer and immunosuppressed patients, and newborns with HIV infections).

Also acknowledged is that there were limited data on complications and sequelae of infection and duration of inpatient care for many pathogens. Expert consensus was used when data gaps were encountered, and so some findings may be subject to bias.

"Large multinational prospective cohort studies are needed to fill the gaps on burden of disease criteria," Getahun and colleagues declare. "In addition, quality surveillance data on antifungal resistance, and evidence on IPC (Infection Prevention and Control) measures are needed to better inform future iterations of the WHO FPPL."

The World Health Organization's fungal priority pathogens list is intended to prompt research, development and policy against the increasing health threat.

WHO Ranks Risks of Invasive Fungal Infections


A novel form of the oral, live virus polio vaccine is being considered by the CDC for an outbreak and ongoing detection of the virus in New York, following a 

 by the Polio Vaccine Work Group at the October meeting of the CDC's Advisory Committee on Immunization Practices (ACIP).

Although vaccination rates have increased in the affected region, Kathleen Dooling, MD, MPH explained to the committee that the injectable, inactivated virus polio vaccine (IPV)—the sole form used in the country since 2000—prevents paralytic infection but not viral transmission, leaving unimmunized populations at heightened risk.

 in Rockland County in June in an unimmunized, immunocompetent young adult, genetically linked poliovirus has been detected in wastewater monitoring in the greater New York City area, most recently (as of October 11) in Brooklyn and Queens.

Typically, clinical illness without paralysis occurs in approximately 25% of infections, and 75% will be asymptomatic. Dooling emphasized, however, that although paralytic polio occurs in less than 1% of infections, a single case indicates an outbreak.

"A single paralytic case implies hundreds (to) thousands of infections," she indicated.

The oral vaccine is effective in limiting spread of the virus by producing intestinal mucosal immunity, while the injection of inactivated virus may only induce some nasopharyngeal mucosal immunity. The live, attenuated virus of the oral vaccine has, however, posed the risk of mutation into virulent form after shedding.

Dooling noted that the newer, novel oral polio vaccine (nOPV2) is more genetically stable, and less likely to be associated with such mutation and infection risk than the earlier formulation. It was approved for use inthe World Health Organization Emergency Use Listing (EUL) in November, 2020.

"Review of safety data on the first 65 million doses of nOPV2 used for outbreak response by the independent Global Advisory Committee on Vaccine Safety (GACVS) concluded that there were no obvious red flags or safety concerns," Dooling indicated.

In addition to the possible use of nOPV2 in areas with outbreaks or persistent circulation of poliovirus, Dooling and the Polio Vaccine Work Group presented the following policy questions for the CDC to consider:

Whether more specific guidance on adult vaccination, including use of adult booster doses, can be provided in the context of circulating poliovirus

Whether adults who are immunocompromised should be recommended an additional adult booster of a polio-containing vaccine.

Whether fractional doses of IPV (fIPV), as prequalified by WHO, should meet polio vaccination requirements, including for people immigrating to the United States

 with Spencer Kimball at CNBC following the committee meeting, Janell Routh, MD, MHS, CDC Medical Officer and Lead, Acute Flaccid Myelitis and Domestic Poliovirus Team, indicated that the decision to employ the oral vaccine will not be made without further deliberation.

"It will be a process. It's not something that we can pull the trigger on and have it appear overnight," she told Kimball. "There will be lots of thought and discussion about the reintroduction of an oral polio vaccine into the United States."

Polio outbreak has CDC Advisory Committee on Immunization Practices considering a novel oral vaccine 20 years after shelving its predecessor.

CDC Considers Reintroducing Oral Form of Vaccine For Polio Outbreak in New York


A potential cure for human immunodeficiency virus type 1 (HIV-1) created with CRISPR-based editing of HIV proviral DNA was well tolerated by the first participant of a phase 1/2 clinical trial, according to an 

 in September by study sponsor, Excision Biotherapeutics.

"It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient, and is expected to enable the first ever clinical assessment of a multiplexed, 

 gene editing approach," said Daniel Dornbusch, CEO of Excision.

The utilization of bioinformatics programs to guide CRISPR genome editing for a potential viral defense, achieving high levels of viral excision while avoiding off-target effects, was 

 at the American Society of Gene + Cell Therapy (ASGCT) annual meeting, May 16-18, 2022.

Investigators described using COTANA (CRISPR-Off-Target Nomination and Analysis) to guide CRISPR-Cas9 editing to produce pairs of guide RNAs (gRNAs) that cleave HIV, with minimal similarity to sites in the human genome. The subsequent application of multiplex amplicon sequencing identified high levels of viral excision without "indels" (unintended insertion/deletion of nucleotides into genomic DNA).

"The COTANA bioinformatics search of the human genome found no identical matches, as there are no target sites in human cells without HIV," reported Thomas Cradick, PhD, Chief Scientific Officer, Excision, and colleagues.

The resulting investigational candidate, EBT-101, was formulated with an adenovirus-associated virus vector serotype 9 (AAV9) to deliver CRISPR-Cas9 generated dual gRNAs to simultaneously target 3 distinct sites within the HIV genome.The investigators anticipate that a single intravenous infusion could produce a clinical cure through excision of large portions of the HIV genome and minimizing viral escape.

 began in January, and is projected to enroll 9 participants (adult males 18-60 years of age) and to evaluate 3 dosage levels. The sponsor also anticipates a study to 

 these participants long-term, with an estimated start in March 2023, and extending into 2037.

Inclusion criteria include documented chronic HIV-1 infection and stable ART regimen for ≥2 years prior to screening; with no interruptions within the last 12 months greater than 14 consecutive days. Exclusion criteria include documented prior HIV-1 drug resistance to ≥2 classes of ART, or history of≥1 change in ART due to virologic failure during preceding 2 years.

The first participant received EBT-101 in July, and, at the time of the September announcement, had tolerated it well.The investigators expect that the participant will qualify for analytical treatment interruption (ATI) of the background antiretroviral therapy (ART) at week 12 after dosing, in an evaluation of a potential cure.

The principal investigator of the phase 1/2 trial, Rachel Presti, MD, PhD, Washington University School of Medicine in St Louis commented in the announcement. 

"Using gene editing to target the HIV DNA reservoirs in human cells is a novel investigational approach, designed to cure HIV," Presti said. "We are well-positioned to collect key data in this first-in-human study, to determine whether we can duplicate the success seen using his approach in animal models." 

CRISPR edit of proviral DNA tested as potential cure for HIV in first participant of phase 1/2 clinical trial.

Kenneth Bender, PharmD, MA

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