Kevin Kunzmann

A version of this article was originally published by our sister site, 

The FDA has granted approval to Pfizer-BioNTech for the tandem’s vaccine BNT162b2 (Comirnaty), a month after giving 

priority review designation to the biologics license application

This indication is for those individuals aged 16 years and older, the indication for which BNT162b2 was originally granted an emergency use authorization (EUA) in December 2020. Currently, those aged 12 to 15 years will still have access to the vaccine through the EUA, and the administration of a third dose is recommended for certain immunocompromised individuals.

“The FDA’s approval of this vaccine is a milestone as we continue to battle the COVID-19 pandemic. While this and other vaccines have met the FDA’s rigorous, scientific standards for emergency use authorization, as the first FDA-approved COVID-19 vaccine, the public can be very confident that this vaccine meets the high standards for safety, effectiveness, and manufacturing quality the FDA requires of an approved product,” Janet Woodcock, MD, acting FDA commissioner, said in a statement.

 “While millions of people have already safely received COVID-19 vaccines, we recognize that for some, the FDA approval of a vaccine may now instill additional confidence to get vaccinated. Today’s milestone puts us one step closer to altering the course of this pandemic in the US.”

The Pfizer/BioNTech inoculation is a nucleoside-modified messenger RNA (mRNA) vaccine encoded with the SARS-CoV-2 full-length Spike protein glycoprotein. It was selected for continued assessment against 3 other candidates by Pfizer and BioNTech investigators in July 2020 and was granted Fast Track Designation by the FDA around the same time.

COVID-19 and MS Summit — Infections and Immunizations in the Era of COVID-19

The approval is particularly promising for the multiple sclerosis (MS) population, as some data have implied a potential increased risk of severe infection and hospitalization for those on 

certain MS disease-modifying therapies (DMTs)

 and that those with MS or neuromyelitis optica spectrum disorder (NMOSD) on some therapies had 

 suggesting that the vaccine has an overall safe profile for patients with MS and should be further confirmed in larger, prospective studies.

Those data, published by Itay Lotan, MD, department of neurology, Rabin Medical Center, and colleagues included 262 patients with MS who responded to the group's survey. Patients first answered general demographic and disease-related questions and were then questioned on vaccination status, date of vaccination, presence, early reactions, and type and timing of new or worsening neurological symptoms following the vaccination. The median age of the cohort was 42 years (range, 22-79 years), with 25.2% (n = 66) of participants reporting associated comorbidities. Disease-modifying therapy (DMT) use was reported in 198 participants (75.6%), while 17 participants received treatment with corticosteroids in the month proceeding the first vaccination. A total of 239 participants (91.2% of responders) received the vaccine, 18 (7.5%) of whom received only 1 dose and 221 (92.5%) participants that received both doses.

Following vaccination, 136 participants (56.9%) reported early adverse events (AEs), with pain at the injection site as the most-reported AE by 111 participants (46.4%). Fatigue (38.1%), muscle pain (36.8%), headache (36.8%), chills (29.7%), fever (15.9%), and dizziness (12.6%) rounded out the other AEs. Among the 198 participants who were treated with DMTs, 100 (55.9%) reported AEs. In comparison, 36 of 57 participants (63.2%) who received the vaccine and were not treated with DMTs reported AEs (

= 0.0683). Sixty-nine of 127 participants (54.3%) treated with DMTs who were younger than 55 years of age experienced AEs, while 23 of the 52-patient cohort (44.2%) above 55 years of age on DMTs reported AEs. Notably, no association between the type of DMT and the frequency and type of AEs was found.

Therapeutic Advances in Neurological Disorders 

 who had received Pfizer’s COVID-19 vaccines and were treated with high-efficacy DMT, finding that only cladribine (Mavenclad; EMD Serono) did not impair humoral response.Protective humoral immunity was demonstrated in 46 of 47 (97.9%) of healthy subjects (n = 47) and untreated patients with MS (n = 32). All patients (100%) treated with cladribine (n = 23) developed a high level of antibodies post-COVID-19 vaccination (

<.0001). Notably, cladribine was the only DMT with a 100% protective humoral immunity rate.

This decision by the FDA comes while new cases of the pandemic virus have reached their highest in the US this year and COVID-19 vaccination rates have nearly plateaued. Several experts in virology and vaccinology explained to 

, that a full FDA approval for a proven COVID-19 vaccine may better public health efforts geared toward curbing the highly transmissible Delta variant of SARS-CoV-2.

As of the week of August 16, the US reportedly had a COVID-19 vaccine surplus of approximately 100 million doses, as Pfizer-BioNTech, Moderna, and Johnson & Johnson developers’ 2020 rush to manufacture now-authorized vaccines was met by a middling national immunization push in 2021. In the same time frame, the country’s 7-day average for new COVID-19 cases has increased 153% from an estimated 60,000 on July 21 to more than 150,000 on August 21. The Δ-variant has been largely to blame for this newest spike in COVID-19 cases, hospitalizations, and deaths. Per the CDC, the now-prominent strain is estimated to be more than 2-fold more contagious than previous SARS-CoV-2 variants, has been linked to more severe illness among unvaccinated persons, and more breakthrough infections in vaccinated persons.

, the Consortium of Multiple Sclerosis Centers, and Can Do MS will be conducting a 90-minute virtual summit where experts in immunology, virology, and neurology discuss infections and MS, the persistence of the SARS-CoV-2 virus, the impact of viral variants, the current vaccine landscape, and DMT guidance in a joint forum tailored for healthcare providers as well as patients and caregivers.

Register for the "COVID-19 and MS Summit – Infections and Immunizations in the Era of COVID-19" broadcast for free below.

REFERENCES
1. FDA Approves First COVID-19 Vaccine. News release. FDA. August 23, 2021. Accessed August 23, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine
2. U.S. FDA Grants Priority Review for the Biologics License Application for Pfizer-BioNTech COVID-19 Vaccine. News release. Pfizer; BioNTech. July 16, 20121. Accessed August 23, 2021. https://investors.biontech.de/news-releases/news-release-details/us-fda-grants-priority-review-biologics-license-application
3. Spelman T, Forsberg L, McKay K, Glaser A, Hillert J. Increased rate of hospitalisation for COVID-19 among rituximab-treated multiple sclerosis patients: A study of the Swedish multiple sclerosis registry.

. July 2021. doi:10.1177/13524585211026272
4. Louapre C, Ibrahim M, Maillart E, et al. Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders. 

. Published online August 2, 2021. doi: 10.1136/jnnp-2021-326904
5. Lotan I, Wilf-Yarkoni A, Friedman Y, Stiebel-Kalish H, Steiner I, Hellman MA. Safety of the BNT162b2 COVID-19 vaccine in multiple sclerosis: early experience from a tertiary MS center in Israel. 

. Published online July 21, 2021. doi:10.1111/ene.15028
6. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. 

. 2021;14: 17562864211012835. doi:10.1177/17562864211012835
7. Kunzmann K. FDA Approves Pfizer-BioNTech COVID-19 Vaccine. ContagionLive. August 23, 2021. Accessed August 23, 2021. https://www.contagionlive.com/view/fda-approves-pfizer-biontech-covid-19-vaccine
8. Delta Variant: What We Know About the Science. CDC. Updated August 19, 2021. Accessed August 23, 2021. https://www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html

Articles

The full approval for BNT162b2 (Comirnaty; Pfizer/BioNTech) will afford physicians greater prescribing capability and is expected to play a role in driving workplace vaccine mandates.

FDA Approves Pfizer COVID-19 Vaccine for Those Ages 16 Years and Older

 on ContagionLive, a sister publication of NeurologyLive. 

 have been reported in women aged 18 to 48 who received Johnson & Johnson's Janssen COVID-19 vaccine, causing the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) to pause administration at federal sites pending a larger investigation. 

Reports of the rare blood clotting disorder were recorded 6 to 16 days following administration of the one-shot adenovirus Ad26.COV2.S vaccine. As of Tuesday morning, 1 woman with the condition has died and a second woman in Nebraska is hospitalized and in critical condition.

Based on this, the federal agencies have advised that states distributing the vaccine also pause their operations.

"We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered," Johnson & Johnson said in a statement. "In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe."

The pharmaceutical company went on to say that "people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider."

The FDA and CDC investigators intend to collaborate on assessment of possible links between the Janssen vaccine and cerebral venous thrombosis in order to discern whether the company’s Emergency Use Authorization (EUA) should continue as-is or become limited.

The FDA reiterated the importance of an indefinite pause during this investigation in a statement shared on Twitter Tuesday morning.

"This is important to ensure that the health care provider community is aware of the potential for these adverse events and can plan due to the unique treatment required with this type of blood clot," 

The CDC’s Advisory Committee on Immunization Practices (ACIP) will hold an emergency meeting on the matter this Wednesday, according to 

Per the CDC, more than 6 million people in the US have received Janssen’s vaccine thus far, and another 9 million doses have been shipped to different states.

Comparatively, Pfizer-BioNTech and Moderna have delivered 23 million-plus doses weekly of their two-dose mRNA vaccines to the US, comprising a significant majority of the US’ vaccine distribution. No significant safety concerns have emerged from either product.

Just last month, the Biden administration 

announced the acquisition of another 100 million doses of Ad26.COV2.S from Janssen

, to be delivered in the latter half of 2021.

 in manufacturing at its Baltimore plant due to the inadvertent mixing of vaccine ingredients. The error resulted in the loss of up to 15 million doses.

The FDA and CDC made the call after 6 reports of the serious blood clot event, which has so far been linked to 1 patient death. 

Johnson & Johnson COVID-19 Vaccine Paused After Reports of Cerebral Venous Thrombosis

 on Contagion, a member of the HCPLive Network. 

The Moderna coronavirus 2019 (COVID-19) vaccine candidate mRNA-1273 has induced immune responses in all 45 of its volunteer patients administered doses in the phase 1, dose-escalation, open-label trial.

 show the vaccine candidate, encoded with a stabilized prefusion 

 spike protein, induced anti-SARS-CoV-2 immune responses in all of the trial’s participants, without any trial-limiting safety concerns identified.

Investigators described the immunogenicity profile of mRNA-1273 as “rapid and robust,” particularly noting the 100-mcg dose vaccine eliciting high neutralization responses, Th1-skewed CD4 T cell responses, as well as a reactogenicity profile more favorable than the observed higher and lower doses.

The findings, reported by the mRNA-1273 Study Group, supports the advancement of a 100-mcg dose vaccine to a phase 3 trial assessment in later summer 2020, while a phase 2 trial of a pair of different doses of the potential vaccine continue among 600 healthy adults.

Moderna, along with The National Institutes of Health (NIH), announced the beginning of the phase 1 trial in mid-March. Investigators sought to assess 3 different doses (25 mcg, 100 mcg, 250 mcg) among 45 volunteer participants in 2 doses injected intramuscularly into the upper arm approximately 28 days apart. Participants were aged 18 to 55 years old.

In mid-May, the US Food and Drug Administration (FDA) granted the vaccine candidate fast track designation.

Neurology Groups Come Together to Support Continued Telemedicine Parity

The team reported that antibody responses were greater among higher doses—as per day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer (GMT)&mdash;after the first vaccination dose. GMTs were 40,227; 109,209; and 213,526 among the 25 mcg, 100 mcg, and 250 mcg groups, respectively.

Following the second vaccination, serum neutralizing activity was detected by 2 methods in all participants. Values were generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.

Adverse events, including fatigue, chills, headache, myalgia, and injection site pain, occurred in a majority of patients. Systemic adverse events were more frequent following the second vaccination dose—particularly among the 250 mcg treatment arm, as 3 reported ≥1 severe adverse event.

Overall, mRNA-1273 showed signs of an immunogenic vaccine, inducing “robust binding antibody responses” to both full-length S-2P and receptor-binding domain in every participant following first vaccination.

“Seroconversion was rapid for binding antibodies, occurring within 2 weeks after the first vaccination, but pseudovirus neutralizing activity was low before the second vaccination, which supports the need for a two-dose vaccination schedule,” investigators wrote.

Though both binding and neutralizing antibody titers induced by the two-dose schedule in participants were similar to those observed by researchers in convalescent serum specimens, they stressed that COVID-19 convalescent antibody titers are variable due to patient age, disease severity, and time since disease onset.

Investigators added to what may be the first sign of an effective vaccine to SARS-CoV-2 a significant benefit of rapid manufacturing through the familiar mRNA platform.

“Product development processes that normally require years were finished in about 2 months,” they wrote. “Vaccine development was initiated after the SARS-CoV-2 genome was posted on January 10, 2020; manufacture and delivery of clinical trials material was completed within 45 days, and the first trial participants were vaccinated on March 16, 2020, just 66 days after the genomic sequence of the virus was posted.”

The discussion of what would constitute a beneficial COVID-19 vaccine for the greater population has been one of debate—yet most experts have given consideration to the variable nature of the virus, its transmission, and effects on patients. The FDA issued a guidance last month stating that preventing disease or at least decreasing disease severity in at least 50% of all vaccinated persons is the bar.

 a month prior, William Schaffner, MD, professor of Preventive Medicine and Medicine at the Vanderbilt University Medical Center, discussed the greater unknown factors of a would-be COVID-19 vaccine—how long would it last? What would be its dosing regimen? Does it require a booster? Is it age-limited?

In setting a mark for overall efficacy, Schaffner was more ambitious than the FDA's guidance.

“We would hope for something that is over 80% effective,” he said. “We have to, I think, in the 21st century, have a product that is at least 80% effective. They would hope for more, of course."

Now that Moderna's phase 3 trial dose has been finalized at 100 mcg, they stated on Tuesday their standing commitment to delivering approximately 500 million doses annually, and potentially up to 1 billion doses annually beginning in 2021.

The findings support the advancement of a 100-mcg dose vaccine to a phase 3 trial assessment in later summer 2020, while a phase 2 trial of a pair of different doses continues among 600 healthy adults.

Moderna COVID-19 Vaccine Shows Promise, Moves to Phase 3

The intravenous quarterly CGRP inhibitor eptinezumab significantly reduced monthly migraine days (MMD) compared with placebo for patients with chronic migraine, according to findings from the 6-month phase III PROMISE 2 trial presented at the 60th Annual American Headache Society (AHS) Scientific Meeting.

In PROMISE 2, there was a reduction of -8.2 monthly migraine days with eptinezumab from baseline versus -5.6 with placebo (

 <.0001). Following 2 quarterly infusions of eptinezumab at 300 mg, 21% of patients experienced a 100% reduction in MDDs. Just 9% of patients in the placebo group experienced this milestone.

“The efficacy data following two quarterly infusions from the PROMISE 2 trial demonstrate eptinezumab’s potential to offer both rapid and sustained suppression of migraine that is further improved for patients whose quality of life is severely impacted by this condition,” lead investigator Richard Lipton, MD, director of the Montefiore Headache Center, Albert Einstein College of Medicine, said in a statement. “My patients could potentially see great benefit from a treatment that can provide the level of efficacy seen with eptinezumab in the clinical studies.”

Additionally, after 2 quarterly infusions, 64% of patients had a ≥50% reduction in migraine days with eptinezumab compared with 44% with placebo. Forty-three percent had a reduction of ≥75% with eptinezumab compared with 24% for placebo.

Alder Biopharmaceuticals, the company developing eptinezumab, announced in January 2018 that the study had met its primary endpoint. Filing of a biologics license application (BLA) is anticipated for eptinezumab in the first quarter of 2019, the company said during a conference call in May.

"Our primary goal is the submission of a high-quality BLA that will meet the U.S. Food and Drug Administration’s requirements for approval and ensure eptinezumab’s successful commercial launch," Paul B. Cleveland, interim president and chief operations officer at Alder, said during the call. "As we committed, we have completed an internal review of all activities related to our BLA and have concluded that we can achieve a high-quality BLA submission in the first quarter of 2019."

In the phase III trial, 1072 patients with chronic migraines were randomized to receive either eptinezumab (300 mg or 100 mg) every 12 weeks or matched placebo. Eligible patients had experienced at least 15 headache days per month—with more than half meeting criteria for migraine. Researchers investigated for primary endpoint of mean change from baseline in monthly migraine days over the 12-week period.

Secondary endpoints included proportion of patients experiencing migraine on the day following treatment administration and reduction of migraine prevalence days 1-28; reduction of at least 50%, 75%, and 100% from baseline in mean monthly migraine days; change in baseline in mean monthly acute migraine therapy days; and reductions from baseline in the Headache Impact Test (HIT-6) impact scores, as reported by patients.

There were no new safety reports seen with the second quarterly infusion, and adverse event (AE) rates among patients administered eptinezumab were similar to those administered placebo. Among the most commonly reported AEs were nasopharyngitis (7.4%), urinary tract infection (2.8%), and nausea (2.5%).

“These data further add to the significant body of clinical evidence supporting eptinezumab’s encouraging clinical profile and reinforce our belief in the value it may provide to patients, if approved” Robert Azelby, chief executive officer of Alder, said in a statement. “The robust efficacy shown over the two quarterly infusions of eptinezumab in chronic migraine patients continues to support eptinezumab’s potential as an important treatment option for patients living with this debilitating condition.”

Eptinezumab, the only drug among the anti-CGRP class to be administered in quarterly infusions, is currently only an investigational monoclonal antibody developed by Alder for migraine prevention. Whether it is eventually approved for marketing in a field of great demand—at least 36 million Americans suffer from migraines&mdash;may hinge on the results of long-term, global trials such as PROMISE 2.

The intravenous quarterly CGRP inhibitor eptinezumab significantly reduced monthly migraine days compared with placebo for patients with chronic migraine.

Quarterly Infusions of Eptinezumab Highly Effective for Migraine Prevention in PROMISE 2

More than two-thirds of patients treated with intravenous infusions of the CGRP inhibitor eptinezumab had an average 50% reduction in migraines, according to 12-month data from the phase III PROMISE 1 trial presented at the AAN Annual Meeting.

For the long-term analysis, patients with episodic migraines were dosed once every 3 months. Through months 6 to 12, 70.7% of patients treated with eptinezumab reported an average reduction of 50% or greater of monthly migraine days from baseline compared with just 58.7% for patients given placebo. The reduction was an 8.9% improvement from mean reductions reported during the first 2 quarterly doses of therapy.

Based on an earlier assessment of the data, Alder BioPharmaceuticals submitted a Biologics License Application to the FDA for eptinezumab. Under the Prescription Drug User Fee Act (PDUFA), the FDA will decide on the application in September 2018.

“I am very excited to see the encouraging results in migraine prevention shown in the PROMISE 1 long-term data,” Stephen D. Silberstein, MD, professor of Neurology and Director of the Jefferson Headache Center, Thomas Jefferson University, said in a statement. “I see a significant need for my patients for a treatment that provides rapid, effective, well-tolerated and long-term results and I’m looking forward to the FDA’s review of these data.”

The original double-blind, placebo-controlled global trial randomized 888 qualified patients to receive either eptinezumab (300 mg, 100 mg, or 30 mg), or placebo infusion, once-weekly for 12 weeks. All patients had previously experienced at least 14 headache days per month, with 4 of such headaches meeting the criteria for migraine.

Primary endpoint for the trial was mean change from baseline in monthly migraine days over the treatment period. Results presented at the AAN meeting focused on the therapy’s extended results through month 12.

At the long-term follow-up, 51.5% of patients treated with eptinezumab reached a mean monthly migraine day reduction of 75% or greater from baseline. Just 38.7% of patients given placebo reported that rate. This represented a 12.8% improvement with extended treatment compared with reports from the first 2 quarterly doses.

The most commonly reported adverse events in all eptinezumab treatment groups were upper respiratory infection (10.5%), nasopharyngitis (6.8%), and sinusitis (3.6%).

Eptinezumab is also backed by another phase III trial (PROMISE 2), in which 1072 patients with chronic migraines were randomized to receive either eptinezumab (300 mg or 100 mg) or placebo, which Alder initially reported was positive in January 2018. This trial also met secondary endpoints of reduction in migraine prevalence day 1 and days 1 to 28 post infusion.

In PROMISE 2, there was a reduction of -8.2 monthly migraine days with eptinezumab versus -5.6 placebo (P <.0001). This represented a 51% reduction in migraines days. Additionally, 61% of patients had a ≥50% reduction in migraine days with eptinezumab compared with 39% with placebo. A third of patients (33%) had a reduction of ≥75% with eptinezumab compared with 15% for placebo.

“These clinically significant data clearly demonstrate that eptinezumab delivered by infusion provided rapid, effective and sustained migraine relief,” Randall C. Schatzman, PhD, president and chief executive officer of Alder. “If approved, eptinezumab has the potential to advance the treatment paradigm in chronic migraine prevention and be a meaningful treatment option for millions of the most severely impacted patients.”

More than two-thirds of patients treated with intravenous infusions of the CGRP inhibitor eptinezumab had an average 50% reduction in migraines.