What my Patients Should Know About the New RSV Vaccine
Adverse events and potential complications with the flu shot
Quick Summary
On May 23, 2023, The U.S. Food and Drug Administration (FDA) approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States (FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine | FDA). This vaccine is approved for prevention of lower respiratory tract disease in adults aged 60 years and older. Interim results for the Northern Hemisphere subjects were recently reported in the New England Journal of Medicine (Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults | NEJM). In terms of RSV-related disease (of any severity), the absolute risk reduction was 0.0026%, so the Number Needed to Treat (NNT) to prevent one case of RSV-Related lower respiratory disease is 1/0.0026 = 385. Meanwhile, there was 1 case of “severe RSV-related lower respiratory tract disease” in the vaccine group and 17 cases in the placebo group, suggesting some efficacy against severe disease.
However, analysis of adverse events shows that systemic reactions were significantly more common in the vaccine group versus those who received the placebo. Additionally, there were 3 deaths in the trial, but blinding to group status has been maintained. Nonetheless, the NEJM article asserts that “the incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.” The NEJM article also makes no mention of the greater association of serious adverse events in the treatment group, including a greater association with atrial fibrillation, but the FDA press release for Arexvy does highlight these concerns. This kind of information is precisely the kind of information needed for informed consent, so why did the authors of the NEJM article neglect to include it? The omission of this information raises serious questions about the integrity of academic medical journals and their seeming cozy relationship to the pharmaceutical industry.
Arexvy Approved for RSV
On May 23, 2023, The U.S. Food and Drug Administration (FDA) approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States (FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine | FDA). This vaccine is approved for prevention of lower respiratory tract disease in adults aged 60 years and older.
Arexvy was developed by GlaxoSmithKline. The FDA evaluated data from an ongoing, randomized, placebo-controlled clinical study in the Northern and Southern hemispheres, including the US. This trial’s interim results were reported for the Northern Hemisphere subjects, in the New England Journal of Medicine (Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults | NEJM). The primary endpoint was RSV-related lower respiratory tract disease as confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). Lower respiratory tract disease was defined as at least two lower respiratory symptoms or signs (including at least one lower respiratory sign) or at least three lower respiratory symptoms lasting for at least 24 hours:
From the Supplementary material, Table S2:
Lower respiratory symptoms: new or increased sputum; new or increased cough; new or increased dyspnea (shortness of breath);
Lower respiratory signs: new or increased wheezing; new or increased crackles/rhonchi base don chest auscultation; respiratory rate > respirations/min; low or decreased oxygen saturation (=oxygen saturation <95% or <90% if pre-season baseline is <95%); need for oxygen supplementation.
For laypeople: symptoms are things that people experience and report to clinicians, and signs are things that clinicians detect on examining a patient; typically one expects many illnesses, especially severe ones, to be diagnosed based on a combination of symptoms and signs.
Study population
26,664 participants aged 60 and older were randomized to receive the vaccine or saline placebo. Mean age was about 70 in both groups (range 65-98); about 40 % had “coexisting conditions of interest”--due to chronic cardiac or pulmonary conditions, kidney or advanced liver disease or diabetes mellitus.
Selected Exclusions (review the Supplementary Appendix pp 7-9 for the full list):
Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., current cancer, HIV) or immunosuppressive/cytotoxic therapy (e.g., cancer chemotherapy, organ transplantation or treatments of autoimmune disorders);
The usual hypersensitivity to any component of the vaccine, also to latex;
“serious or unstable chronic illness”;
“Any history of dementia or any medical condition that moderately or severely impaired cognition”;
Administration of long-acting immune-modifying drugs or planned administration at any time during the study period (e.g., infliximab);
Chronic administration (defined as more than 14 consecutive days in total) of immunosuppressants or other immune-modifying drugs during the period starting 90 days prior to the first study vaccine administration or planned administration during the study period. For corticosteroids, this meant prednisone > 20 mg/day, or equivalent.
Results
RSV-related lower respiratory tract disease occurred in 40 of 12494 placebo participants (0.0032%) and 7 of 12,466 vaccine recipients (0.0006%). This is an absolute risk reduction of 0.0026%, so the Number Needed to Treat (NNT) to prevent one case of RSV-Related lower respiratory disease is 1/0.0026 = 385.
Also assessed was efficacy against “severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator)”. There was 1 case of this in the vaccine group and 17 cases in the placebo group. These people apparently needed treatment with supplemental oxygen or other intervention, however it is not clear how many, if any, were hospitalized, and it does not appear that there were any deaths due to RSV in the study participants.
Adverse Events
Systemic reactions were significantly more common in the vaccine recipients versus those who got the placebo: fever, headache fatigue, myalgia, arthralgia; also pain, erythema and swelling at the injection site.
There were 3 deaths that were “fatal serious adverse event related to vaccine or placebo”—not known which group the deceased participants belonged to as the blinding to group status was maintained.
The journal article abstract asserts that “the incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups”.
Neither the NEJM article nor its Supplementary Appendix contain information that might raise concerns about potential serious adverse events, however the FDA News Release does ( FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine | FDA ) :
1) “Among all clinical trial participants, atrial fibrillation within 30 days of vaccination was reported in 10 participants who received Arexvy and 4 participants who received placebo … although not a FDA requirement, the company committed to assess atrial fibrillation in the post-marketing study”;
2) “In two other studies, approximately 2,500 participants 60 years of age and older received Arexvy. In one of these studies, in which some participants received Arexvy concomitantly with an FDA-approved influenza vaccine, two participants developed acute disseminated encephalomyelitis (ADEM), a rare type of inflammation that affects the brain and spinal cord, seven and 22 days, respectively, after receiving Arexvy and the influenza vaccine. One of the participants who developed ADEM died. In the other study, one participant developed Guillain-Barré syndrome (GBS) (a rare disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) nine days after receiving Arexvy.”
These are very concerning adverse events; atrial fibrillation is a significant diagnosis that is typically associated with symptoms of palpitations, sometimes shortness of breath, heart failure, dizziness or rarely even syncope (the medical term for a reversible loss of consciousness), and increases a person’s chance of suffering a stroke. People who suffer this require healthcare, and pharmacologic interventions.
Arexvy and the Flu Shot
In addition, the fact that 2 participants who received both a flu shot and Arexvy suffered severe neurologic side effects is frightening. Here’s why: RSV season is Oct 1st to April 1st in the Northern Hemisphere, and this coincides substantially with what I call the “flu shot season”—mid-August to April 1st where I work in the Pacific Northwest. Potentially millions of elders could receive both of these shots. I personally would not want my patients to get both a flu shot and Arexvy due to these data, yet that is exactly what will likely happen if Arexvy is marketed widely next fall. And what about the Covid shot—it is expected that one of these will be recommended also (House COVID panel requests briefing on fall vaccine plans from new CDC head (msn.com)). Getting both Covid and Flu shots is already being promoted to the elderly Can You Get Your COVID-19 Booster With Your Flu Shot? (aarp.org) , and many will go straight to their pharmacies to do this. I cannot tell from the text whether the Arexvy study patient suffering GBS also got a flu shot along with Arexvy, but one estimate of incidence of GBS is 1-2 cases per 100,000 Guillain-Barré syndrome incidence in a large United States cohort (2000-2009) - PubMed (nih.gov).
Why is this AE information in the news release, but not the peer-reviewed article or even its supplement? I believe this is the sort of information patients may want, in considering getting Arexvy; will it be made available to them? I am sharing it with my patients—I have become ever more cautious about new medical interventions in our post-Covid world. I tell patients we have NO long-term data on the safety of these new vaccines, and the studies supporting Arexvy are very short on even good short-term data that it prevents outcomes that matter to me—hospitalization or death due to RSV, or all-cause mortality.
"Systemic reactions were significantly more common in the vaccine recipients versus those who got the placebo: fever, headache fatigue, myalgia, arthralgia; also pain, erythema and swelling at the injection site."
So they know which participants had reactions?
"There were 3 deaths that were “fatal serious adverse event related to vaccine or placebo”—not known which group the deceased participants belonged to as the blinding to group status was maintained."
But not if they died?
These two statements seem contradictory...
12466 vaccine recipients, with an NTT of 385, means they "treated" 32 people. Unknown how many of them would have died from RSV, I think it's safe to assume that they killed 3. Kill 3 to "treat" 32...
I don't trust the study. I don't trust the FDA. I wouldn't recommend this. But I'm no "expert"...
RSV first appeared as a chimpanzee respiratory virus where chimp renal cells were cultured to produce the human polio vaccines in the late 50s. RSV is a new name as calling it a chimp virus secondary to a polio vaccine would frighten the populace. Initially, this chimp virus killed quite a few people, but likely over the last 70 years it has modified itself to become more infectious and less lethal. Creating a vaccine to cover another vaccine complication with no liability for the producer of either vaccine for me speaks of risk. The true adverse reactions to Covid vaccine have yet to be revealed