FDA Expands Emergency Use for Lilly Antibody Combo for Covid-19 to Include Infants

 The U.S. Food and Drug Administration expanded its emergency use authorization for a combination of two Eli Lilly & Co. monoclonal antibodies for treating mild to moderate Covid-19, expanding authorization to all ages including newborns for those who are at high risk for progression to severe Covid-19.

The combination of bamlanivimab and etesevimab was previously authorized for people 12 years of age and older weighing at least 40 kilograms.

Lilly said it is "working quickly to understand neutralization activity of our therapies on the Omicron variant of concern."

https://www.marketscreener.com/quote/stock/ELI-LILLY-AND-COMPANY-13401/news/FDA-Expands-Emergency-Use-for-Lilly-Antibody-Combination-for-Covid-19-to-Include-Infants-37207727/

New Type of Hepatitis B Vaccine OK'd

 The FDA approved the first three-antigen hepatitis B vaccine (PreHevbrio) to prevent infection from all known subtypes in adults, VBI Vaccines announced on Wednesday.

Approval for the recombinant vaccine -- which contains the S, pre-S1, and pre-S2 hepatitis B virus (HBV) surface antigens -- was based on data from two phase III trials that compared the safety and immunogenicity against the single-antigen Engerix-B vaccine.

In PROTECT, the three-antigen vaccine demonstrated higher seroprotection rates versus Engerix-B among all adults (91% vs 77%, respectively) and among those 45 and older (89% vs 73%). In CONSTANT, a pooled analysis of adults who received PreHevbrio had numerically higher seroprotection rates compared to the Engerix-B group (99% vs 95%).

Last month, the Advisory Committee on Immunization Practices (ACIP) recommended that all adults ages 59 and younger, and adults ages 60 and up who have risk factors for HBV, be vaccinated against HBV.

"As we work to implement the ACIP's new universal hepatitis B vaccine recommendation for all adults ages 19-59, as voted on in November, we benefit from having more tools, including this newly approved three-antigen hepatitis B vaccine," said Chari Cohen, DrPH, MPH, of the Hepatitis B Foundation, in a statement from VBI Vaccines's announcement.

"Having more vaccine options will help us effectively expand vaccine uptake, ensure more people are protected from hepatitis B infection, and reach the 2030 goal of eliminating hepatitis B in the U.S.," she added.

The PreHevbrio vaccine series involves three intramuscular injections, with the second and third doses given at 1 and 6 months. Single-dose vials (1.0 mL) of the product are expected to be available within the first quarter of 2022.

According to the label, the vaccine is contraindicated for patients with a history of anaphylaxis after previously receiving any HBV vaccine.

Common adverse events with the three-antigen vaccine include injection site pain and tenderness, as well as systemic reactions such as fatigue, headache, and myalgia, "all which generally resolved without intervention in 1-2 days," VBI Vaccines stated.

Immunocompromised patients may experience a diminished response, and adults with an unrecognized HBV infection at the time of receiving the vaccine may not be protected, the company noted.

https://www.medpagetoday.com/gastroenterology/hepatitis/95983

Dementia Tied to Resting Heart Rate

 Higher resting heart rate (RHR) was linked to greater dementia risk and faster cognitive decline independent of cardiovascular disease in a study of more than 2,000 older adults in Sweden.

People with RHR of 80 bpm or higher had a 55% increased risk of developing dementia compared with people whose RHR was 60-69 bpm (adjusted HR 1.55, 95% CI 1.06-2.27), reported Yume Imahori, MD, PhD, of the Karolinska Institutet in Stockholm, and co-authors.

The association remained significant after excluding people with prevalent and incident cardiovascular disease. Cognitive function scores fell over time in all RHR groups, but people with RHR of 80 bpm or higher declined more quickly than people with RHR of 60-69 bpm, Imahori and co-authors wrote in Alzheimer's & Dementia.

Previously, the Atherosclerosis Risk in Communities (ARIC) study showed that an RHR of 80 bpm or more in midlife raised the risk of cognitive decline and incident dementia as people aged.

"Our study showed that this finding was also applicable in RHR measured in late life," Imahori told MedPage Today. "It further revealed that this association was not due to underlying cardiovascular diseases such as atrial fibrillation and heart failure."

"This study is important because RHR might be used to identify older people with a potentially high risk of cognitive decline in a wide variety of settings," Imahori added.

"If cognitive function in patients with elevated RHR is followed carefully and early intervention is made, the onset of dementia might be delayed, which can have a substantial impact on patients' quality of life," she said. "If further studies show that this association is causal, reducing RHR might be considered as a target of intervention."

Imahori and colleagues followed 2,147 older adults (62.1% women) in the Swedish National Aging and Care in Kungsholmen (SNAC-K) population-based study with a mean baseline age about 71. All participants were dementia-free at baseline and followed regularly from 2001-2004 until 2013-2016. Cognition and dementia status were assessed at multiple timepoints. Baseline mean Mini Mental State Examination (MMSE) score was 29.0 and was similar across RHR groups.

Mean RHR, obtained from a standard 12-lead ECG at baseline, was 65.7 bpm. Participants in higher RHR groups were older (mean age about 72), less educated, and were more likely to be current smokers, physically inactive, and hypertensive. Prevalence of cardiovascular disease -- ischemic heart disease, atrial fibrillation, heart failure, or stroke -- at baseline was not significantly different among RHR groups.

Over a median followup of 11.4 years, 289 people were diagnosed with dementia. High RHR remained associated with dementia after excluding people with baseline cardiovascular disease and those who developed cardiovascular disease during followup.

MMSE scores fell faster for people who had high RHR. Compared with a resting rate of 60-69, RHR of 80 or more was associated with annual declines in MMSE score (adjusted β -0.13, 95% CI -0.21 to -0.04); results were similar after excluding prevalent and incident cardiovascular disease. RHR 70-79 also was linked to accelerated drops in MMSE score (adjusted β -0.10, 95% CI -0.17 to -0.04).

The relationship between elevated RHR and cognition might in part reflect pathophysiological pathways independent from vascular risk factors, Imahori and colleagues observed. "Nevertheless, we cannot rule out the possibility that subclinical or undiagnosed cardiovascular diseases may contribute to this association," they wrote.

"This population-based cohort study suggests higher resting heart rate is associated with increased risk for dementia and faster cognitive decline, further adding to the growing body of research showing the health of the heart and brain are closely connected," noted Claire Sexton, DPhil, director of scientific programs and outreach at the Alzheimer's Association in Chicago, who wasn't involved with the research.

"However, this study only shows a correlation between resting heart rate and cognition, not causation," Sexton cautioned. "More research is needed."

Imahori added that caution is needed when generalizing findings to other populations "because our study included mainly Caucasians who had relatively high socioeconomic status."

Unmeasured confounders and selective survival bias might also have influenced associations in the SNAC-K cohort, the researchers acknowledged.

Disclosures

SNAC-K is supported by the Swedish Ministry of Health and Social Affairs and the participating county councils and municipalities, along with additional grants from the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare.

Imahori had no disclosures. Other researchers reported relationships with AFA-Insurance, Carl Bennet AB, FORMAS, FORTEO, Strategic Research Area Epidemiology Karolinska Institute, and the International Society for Environmental Epidemiology.

Primary Source

Alzheimer's & Dementia

Source Reference: Imahori Y, et al "Association of resting heart rate with cognitive decline and dementia in older adults: a population-based cohort study" Alzheimer's Dement 2021; DOI: 10.1002/alz.12495.

https://www.medpagetoday.com/neurology/dementia/95999

Getting COVID Antiviral Pills Into Patients' Hands

 In the coming days and weeks, the FDA will decide whether to provide emergency use authorization to two new antiviral pills for COVID-19 from Merck and Pfizer, which have shown moderate or strong efficacy (respectively) in studies to date, in the reduction of hospitalization or death. The decision on Merck's pill -- molnupiravir -- will likely come first, following a vote yesterday from an expert committee narrowly recommending FDA authorize the treatment for high-risk adults.

Unlike prior treatments, which required injections or were only used to treat hospitalized patients, these medications -- if one or both are authorized -- would be available as simple oral medications. Although the drugs won't reduce the spread of the virus, they may offer a path out of the extreme death and disease caused by the virus.

These drugs have been rightfully hailed as a medical breakthrough. Despite the full analysis of molnupiravir showing the drug isn't as effective as originally believed, the efficacy of the Pfizer drug still appears high. With tens of millions of Americans still unvaccinated and case numbers ticking up again in parts of the country, these treatments have the potential to save many lives.

As with every medical breakthrough, however, there is the looming problem of lack of access. The pandemic exposed time and again the unequal access and unequal outcomes in the American healthcare delivery system. It was critical to scale testing to anyone who needed it in the early days, and we couldn't. It's critical now to get shots in arms, but we're still struggling to do so. Our broken healthcare delivery system -- not scientific innovation -- is the bottleneck.

These new antiviral drugs will challenge our healthcare delivery system even more. To be effective, individuals must take them within the first 3 to 5 days of symptom onset, with even higher efficacy if they are taken sooner. Like nearly all new drugs, the medication will require a physician's prescription. That sounds simple enough: if someone has COVID-19 symptoms, they can get tested, and if positive, their doctor orders the medication. But the reality isn't that simple.

As a practicing primary care physician for the underserved, I know all too well the realities on the ground. A full 25% of Americans don't have a primary care physician. Even for those with access, the wait time for primary care is often days to weeks -- well outside of the narrow time window for the antiviral medications. In many parts of the country, rapid antigen tests for COVID-19 are out of stock and the wait time to process PCR tests is 2 to 3 days.

The problem is even greater in socially marginalized communities with large populations of people of color, members of the LGBTQ+ community, and those in rural areas without nearby care -- the same populations disproportionately affected by COVID-19 cases and death, and with the lowest rates of vaccination.

To overcome these challenges, we need to pair biomedical innovation with delivery system innovation. We need new care models to improve timely and equitable access, just like we did by administering COVID-19 tests in drive-thrus and community testing sites, and by getting shots into arms at pop-up vaccination sites, nursing homes, and pharmacies.

Here are the steps we need to take immediately:

Expand access to telehealth. Telehealth's on-demand nature makes it highly suitable to distribute the antiviral medications (if authorized) within the requisite 3- to 5-day window from symptom onset or diagnosis. To further reduce costs, physicians can prescribe the medication without a synchronous visit, which means a single physician can care for hundreds of patients in a day instead of dozens. Telehealth dramatically expanded during the pandemic, but restrictions such as poor reimbursement and requiring physicians to hold licenses in the state in which they are practicing are already limiting access to medically underserved areas. Moreover, the digital divide -- broadband connectivity, device access, and digital literacy -- will need to be addressed to ensure telehealth improves equitable access to care, or at least does not worsen it.

Enable non-physicians to prescribe the pill(s). If someone tests positive for COVID-19 at a pharmacy or community testing site they would need to make an appointment to see a doctor to get the medication prescribed (if authorized). This creates unnecessary delays in care and adds the expense and inconvenience of a doctor's visit, which disproportionately impacts socially marginalized communities. Instead, we should allow pharmacies, community testing sites, and public health departments to dispense the medication directly -- without a physician visit -- based on a positive COVID-19 result and a questionnaire to understand their medical history and indications for treatment.

Consider fast-tracking the medications as over-the-counter (OTC). The typical process for a prescription drug to become available OTC is usually 3 to 6 years. We don't have that long. Generally, drugs can become OTC if they can be used safely and effectively without a healthcare provider's instruction, have a low potential for misuse and abuse, and are used for self-diagnosed conditions. Just like people can now walk into a pharmacy and pick up a COVID-19 test, they should be able to get antiviral medication for COVID-19 on the shelf. More safety and efficacy testing for the medications will need to be completed before this can happen, but speeding up the typical OTC approval process is paramount to access.

These delivery system innovations will need to be enabled by price support. The medications are expected to cost hundreds of dollars per treatment. While insurance companies will likely cover it, many Americans are underinsured or uninsured.

The country rallied to get shots in arms. It's time for us to rally again to get pills in hands.

Shantanu Nundy, MD, MBA, is a practicing primary care physician, author of Care After Covid: What the Pandemic Revealed Is Broken in Healthcare and How to Reinvent It, and chief medical officer at Accolade, a personalized healthcare company, which provides telemedicine services to employers and consumers.

https://www.medpagetoday.com/opinion/second-opinions/95958

Don't Jump the Gun on Boosting All Adults

 In the wake of the discovery of the Omicron variant of COVID-19, the CDC modified its guidance on booster vaccines. The agency now says that all adults should get a booster vaccine dose if at least 6 months have passed since their initial mRNA vaccine series (or 2 months for Johnson & Johnson recipients). For some time, there have been differing opinions over the benefit of universal boosting, especially for healthy younger individuals. Now it is important to consider whether Omicron changes the calculus.

A booster dose has clearly been demonstrated to be beneficial for certain populations. However, the net benefit of rushing to boost the average healthy person is less clear, especially in the context of the potential need for an Omicron-specific vaccine in the near-term and considering the global fight against COVID-19, which depends on first and second doses.

Studies have established, unsurprisingly, that a booster dose increases antibody levels and is, at least temporarily, likely to stave off a breakthrough infection. But with a destined-to-be endemic coronavirus, a breakthrough infection (symptomatic or asymptomatic), especially with our current vaccines, is likely for most people. For those at heightened risk for severe COVID-19, preventing a breakthrough infection from becoming severe is very important. Anyone over 65 or who has underlying conditions should be boosted as soon as possible. But for most people who are not at high-risk for severe COVID-19, any breakthrough infection will be unlikely to cause severe illness, hospitalization, or death. Therefore, for the young, healthy population, the value of boosting with the vaccine currently available to transiently prevent what would likely be non-severe illness is, to me, of marginal value. The likelihood of non-severe COVID-19 in young, healthy people is almost certain to be as true for Omicron as it has been for Delta, and we will learn more in the coming days and weeks.

For the CDC, however, the appearance of Omicron with its mutation profile, which includes changes that have been associated with less protection from the vaccine, was enough to universalize stronger booster recommendations for all adults. However, this action appears to be a preemptive move done without any new publicly released data to undergird it. The likely rationale behind the change may be that higher antibodies, even against an evasive variant like Omicron, may prevent infection. Though this is plausible, there isn't data yet to support this. But, again, a breakthrough infection with Alpha, Beta, Delta, Lambda, Epsilon, Gamma, or Omicron is still most likely a non-severe COVID-19 infection and will likely be less contagious than infection in an unvaccinated person who, as South Africa is reporting, are more likely to test positive for this variant. The non-severe nature of breakthrough infections is a testament to the success of the vaccines at preventing what matters: serious illness, hospitalization, and death.

Even if the Omicron variant does prove to evade some of the protection engendered by our current COVID-19 vaccines, it is extremely unlikely that this variant can erase everything a vaccine does -- especially the most important attribute: protection against serious illness. These vaccines give us a panoply of immune protection, including the extremely critical (but hard to measure) T-cell immunity. Early (albeit limited) data from South Africa does seem to support that the majority of those hospitalized are not vaccinated.

If Omicron is indeed confirmed to be a major problematic variant, a specific variant-targeted booster will need to be developed. Vaccine manufacturers are reportedly already working on this. While there have been no safety indications to getting a booster dose to date, Paul Offit, MD, Marion Gruber, PhD, MS, and Philip Krause, MD, write in The Washington Post:

"...'training' the immune system repeatedly on the original variant -- as the current boosters do -- may prove to be counterproductive. It could, for instance, diminish the effectiveness of a reformulated booster. In other words, for those not in immediate need of a boost, there may be an advantage to waiting until a booster more closely aligned with circulating variants becomes available."

What they are referring to is a fascinating phenomenon called "original antigenic sin" in which the immune system will respond to a pathogen in a way shaped by its first exposure to it regardless of how the pathogen may have changed. This could blunt the response to altered boosters (an Omicron-specific booster, for example) because when the boosters activate the immune system, the original response is recalled and hampers the ability of immunity more specific to the new version of the pathogen from being developed. The late DA Henderson, MD, MPH -- the architect and commander in chief of the only successful attempt to eradicate a human infectious disease from the planet, and the founder of the Johns Hopkins Center for Health Security -- and I wrote about original antigenic sin and how it explained the patterns of severe illness during the 2009 H1N1 influenza pandemic. In the context of Omicron, it's worth considering how original antigenic sin factors into discussions of boosting young, healthy adults with the current COVID-19 vaccines.

Finally, the emergence of Omicron demands renewed attention to the global fight against COVID-19. The new variant emerged in an area of the world with very low vaccination rates (only a quarter of the South African population is fully vaccinated, for example). This is not surprising. COVID-19 will continue to pose a threat as long as there remain pockets of unvaccinated people in the U.S. and around the world. First and second doses determine the trajectory of the pandemic. This is where the focus must remain. If all healthy 18- to 50-year-olds were boosted in the U.S., Omicron would still have emerged. Prioritizing first and second doses for people who remain unvaccinated around the world is key.

Omicron, which merits much study and characterization, illustrates that until the world has baseline immunity to this virus through vaccination, COVID-19 will continue to be a deadly and disruptive force.

Amesh Adalja, MD, is a senior scholar at the Johns Hopkins Center for Health Security and a practicing infectious disease, critical care medicine, and emergency medicine physician.

https://www.medpagetoday.com/opinion/second-opinions/95973

1 n 44 U.S. children diagnosed with autism, new data suggests

 New autism numbers released Thursday suggest more U.S. children are being diagnosed with the developmental condition and at younger ages.

In an analysis of 2018 data from nearly a dozen states, researchers at the Centers for Disease Control and Prevention found that among 8-year-olds, 1 in 44 had been diagnosed with autism. That rate compares with 1 in 54 identified with autism in 2016.

U.S. autism numbers have been on the rise for several years, but experts believe that reflects more awareness and wider availability of services to treat the condition rather than a true increase in the number of affected children.

A separate CDC report released Thursday said that children were 50 percent more likely to be diagnosed with autism by age 4 in 2018 than in 2014.

“There is some progress being made and the earlier kids get identified, the earlier they can access services that they might need to improve their developmental outcome,” said CDC researcher and co-author Kelly Shaw.

Geraldine Dawson, director of Duke University’s Center for Autism and Brain Development, said the new estimate is similar to one found in research based on screening a large population of children rather than on those already diagnosed. As such, she said it may be closer to reflecting the true state of autism in U.S. children than earlier estimates.

The CDC reports are based on data from counties and other communities in 11 states — some with more urban neighborhoods, where autism rates tend to be higher. The rates are estimates and don’t necessarily reflect the entire U.S. situation, the authors said.

Autism rates varied widely — from 1 in 26 in California, where services are plentiful, to 1 in 60 in Missouri.

Overall, autism prevalence was similar across racial and ethnic lines, but rates were higher among Black children in two sites, Maryland and Minnesota. Until recently, U.S. data showed prevalence among white children was higher.

At a third site, Utah, rates were higher among children from lower-income families than those from wealthier families, reversing a longstanding trend, said report co-author Amanda Bakian, a University of Utah researcher who oversees the CDC’s autism surveillance in that state.

Bakian said that likely reflects more coverage for autism services by Medicaid and private health insurers.

https://www.nbcnews.com/news/us-news/one-44-us-children-diagnosed-autism-new-data-suggests-rcna7485

How Well Do COVID Vaccines Mix and Match Together?

 A "mix and match" booster strategy with a variety of different COVID-19 vaccines was safe and boosted immune response following primary series vaccinations with either Pfizer or AstraZeneca's shots, U.K. researchers found.

In addition to Pfizer and AstraZeneca, the study found acceptable immune responses and safety profiles among five other vaccines when used as boosters after the two-dose Pfizer or AstraZeneca primary series (Moderna, Johnson & Johnson, Novavax, Valneva, CureVac), reported Saul Faust, MD, of NHS Foundation Trust in Southampton, England, and colleagues in The Lancet.

"The side effect data show all seven vaccines are safe to use as third doses, with acceptable levels of inflammatory side effects like injection site pain, muscle soreness, fatigue," said Faust in a statement. He noted that all seven vaccines boosted spike protein immunogenicity after the AstraZeneca primary series, and all vaccines but Valneva did so after the Pfizer primary series. Boosters in the study were given a few months after the primary series.

The FDA approved heterologous "mix and match" boosters in October. However, this decision was made on the basis of preprint data that was not peer-reviewed. CDC currently recommends that all adults receive a booster dose of COVID vaccine at least 6 months after a Pfizer or Moderna two-dose primary series or at least 2 months after a Johnson & Johnson primary shot.

Faust's group conducted the phase II COV-BOOST trial in adults ages 30 and up who were at least 70 days post-AstraZeneca vaccine or 84 days post-Pfizer vaccine and had no history of laboratory-confirmed COVID-19. They were split into three groups, and each group was randomized to either vaccine or control arms.

• Group A received Novavax, half-dose of Novavax, AstraZeneca, or placebo (MenACWY vaccine)
• Group B received Pfizer, Valneva, half-dose of Valneva, Johnson & Johnson, or placebo
• Group C received Moderna, CureVac, half-dose of Pfizer, or placebo

From June 1 to June 30, 2,878 participants met eligibility criteria. They were divided into groups by age: 30 to 69 and 70 and up. Median age in the younger age group was 51 to 53, and in the older age group, it was 76 to 78. Nearly all were white.

Not surprisingly, reactogenicity was greater in adults ages 30 to 69 compared with those ages 70 and up. Fatigue and headache were the most common systemic reactions. Interestingly, those in the Pfizer group who were boosted with Moderna, CureVac, AstraZeneca, or Johnson & Johnson reported more local and systemic reactions than other vaccines and control.

Of 912 participants, 1,306 adverse events were reported, including 20 adverse events of special interest occurring within 14 days after the third dose, six of which were "possibly" related to the vaccine. There were 24 serious adverse events, and 21 participants reported a positive PCR test for SARS-CoV-2, with no hospitalization.

Geometric mean titers increased in all participants at 28 days post-vaccination versus controls for anti-spike IgG, with increases ranging from 1.3 for a half-dose of Valneva to 11.5 for Moderna following a Pfizer primary series.

Examining T-cell response, Faust's group noted that the T-cell boosting effects of Novavax and half-dose of Novavax were lower in those who received a Pfizer versus an AstraZeneca primary series, adding, "The geometric mean of T-cell responses in the half [Novavax] group was not significantly higher than control."

They said there was a "good correlation" for all vaccines between the pseudoneutralizing assay against the wild-type and Delta variants at day 0 and 28.

"Vaccines that produce antibodies against wild-type appear to neutralize Delta effectively in vitro to a consistent, but slightly lesser degree, confirming the current public health strategy of using wild-type vaccines to control the currently predominant Delta epidemic," they wrote.

They also noted that half-doses of vaccines had "minimal decrease on immunogenicity by anti-spike IgG and neutralizing assays."

"If immunogenicity can be maintained in larger dose reduction studies, this could significantly increase the numbers of doses available globally," they added.

Limitations to the study included a shorter interval from second doses to boosters, given the need to generate policy data, as well as a lack of generalizability to younger populations. These results are applicable only in a 28-day timeframe, Faust and colleagues said.

"Further work will generate data at 3 months and 1 year after people have received their boosters, which will provide insights into their impact on long-term protection and immunological memory," Faust said. "We are also studying two of the vaccines in people who had a later third dose after 7-8 months, although results will not be available until the new year."

Disclosures

This study was supported by the UK Vaccine Taskforce and National Institute for Health Research.

Faust acts on behalf of University Hospital Southampton National Health Service Foundation Trust on vaccine clinical trials from Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva.

Other co-authors disclosed support from AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi, Valneva, Boehringer Ingelheim, Chiesi, Cipla, Teva, Medicago, and Novavax.

One co-author is named as inventor on a patent on an ingredient in the AstraZeneca vaccine.

Primary Source

The Lancet

Source Reference: Munro APS, et al "Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial" Lancet 2021; DOI: 10.1016/S0140-6736(21)02717-3.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/95988