A trajectory of the FDA approval of the first vaccine targeting RSV: A greek tragedy with a happy ending

In this issue of the Proceedings, the article by Frenkel et al.¹ provides a prescient background for the recent May 3, 2023, approval by the U.S. Food and Drug Administration (FDA) of the first respiratory syncytial virus (RSV) vaccine for use in the United States.² The vaccine is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older. Most recently, an FDA advisory panel voted on May 18, 2023, in favor of FDA approval of an RSV vaccine developed by Pfizer given to pregnant women to prevent RSV infection in infants.³ These events mark a significant milestone in the history of RSV vaccine development, which is described in detail in the Frenkel et al.¹ article.

The discovery of RSV can be traced back to 1956 when Dr. Morris, at Walter Reed, and colleagues first isolated the virus from chimpanzees.⁴ In 1957, RSV was isolated from infants with respiratory infections by Chanock et al.,⁵ and, by the early 1960s, researchers had developed a formalin-inactivated RSV vaccine, which was evaluated in clinical trials in infants. However, the well-intentioned but ill-fated use of this vaccine rather than providing protective immunity resulted in severe adverse effects, including two deaths, and RSV vaccine development was halted for the next 60 years. This tragedy of the 1960s underscored the need for a better understanding of the molecular biology of RSV.

Over the following decades, researchers, including Dr. Barney Graham, Dr. Jason McLellan, and Dr. Peter Kwong, performed critical studies that allowed for the identification of the prefusion F protein as a vaccine target and helped jump-start the field after decades of failure.^6,7 These studies led to the discovery that the fusion (F) protein, specifically the prefusion form, was key not only to an understanding of the mechanism(s) of vaccine injury in the ill-fated clinical trials in infants but also provided a pathway for the development of a safe and effective vaccine. The prefusion F protein is the antigenic target of the new RSV vaccine approved by the FDA, and its development represents a significant advance in vaccine technology. The basis for the FDA approval was founded on the results of a large clinical trial of an RSV-prefusion F protein vaccine performed in older individuals, which showed 83% protection against RSV pulmonary infection with even stronger protection against severe illness.⁸ The FDA approval of this RSV vaccine represents the first of other RSV-related drugs that are under consideration, including the recent FDA advisory panel recommendation³ for a maternal RSV vaccine to be given during pregnancy that will protect infants from developing severe symptoms during the first 6 months after birth as well as monoclonal antibody preparations for treatment of infants that will offer vaccine-like protective immunity during the winter RSV season.⁷

The story of RSV vaccine development shares some similarities with a Greek tragedy in that both involve a sequence of events that led to a disastrous outcome, followed by a period of reflection, learning, and eventual resolution. The RSV trajectory involves a sequence of events that began with a well-intentioned effort to protect infants from a serious disease but that ultimately led to unintended harm and tragedy. However, unlike a Greek tragedy, which inevitably led to a disastrous outcome and typically ended with the death of the protagonist, the story of the RSV vaccine has a hopeful and presumably happy ending with the approval of a safe and effective vaccine that has the potential to save countless lives. The discovery that the F protein, specifically the prefusion form, was key, which not only provided an understanding of the mechanism(s) of vaccine injury in the ill-fated clinical trials in infants but also illuminated the pathway for developing a safe and effective vaccine. The approval of the RSV vaccine represents the culmination of decades of research and development, and is a testament to the perseverance and dedication of scientists and clinicians. As allergist/immunologists, we are indebted to the efforts of those scientists and clinicians who persevered for 60 years to achieve this success and who laid the groundwork for a better understanding of mechanisms and adverse effects of future vaccines.

In continuing on to an overview of other topics in this issue of the Proceedings, three papers address the topic of asthma biomarkers, each with its own specific focus. Kuai and Zhao⁹ performed a meta-analysis to study the association of eosinophil-derived neurotoxin (EDN) levels in patients with asthma and its correlation with the percentage of forced expiratory volume in the first second of expiration (FEV₁%). A total of 14 articles were selected. The authors report that EDN levels were elevated in patients with asthma compared with controls and were negatively correlated with FEV₁% in patients with asthma, which thus indicates that EDN could be a reliable marker. Wang et al.¹⁰ sought to determine if total serum immunoglobulin E (tIgE) could predict allergic asthma in childhood and to provide a reliable reference value. The diagnosis efficiency of tIgE was validated in 491 children with asthma. The authors conclude that tIgE is an effective predictor for diagnosing allergic asthma in childhood asthma, with tIgE = 96.25 IU/mL being the recommended limit. The research of Hu et al.¹¹ focused on the clinical value of serum soluble receptor for advanced glycation end products (sRAGE) levels in evaluating the severity of bronchial asthma (BA). Blood eosinophils, FEV₁, and serum sRAGE expression were measured in 120 patients with BA, 40 patients with non-BA pulmonary disease, and 40 healthy controls. Serum sRAGE expression levels were found to be negatively correlated with EOS counts, but significantly positively linked to FEV₁ levels. The authors conclude that the serum sRAGE level has potential value in diagnosing the severity of BA.

Three papers in this issue address the importance of aeroallergens in respiratory disease. Brake et al.¹² performed a scoping review with the goal of summarizing the available literature on the factors that affect pollen counts, allergenicity, and thresholds that induce symptoms in individuals who are sensitized. This review identified that several environmental factors correlate with pollen counts and allergen load, including distance from the source, wind characteristics, pollen size, terrain, urban environments, air composition (particulate matter, CO₂ levels, ozone, NO₂), and weather conditions (humidity, thunderstorms, precipitation). Their work not only found that pollen thresholds for the induction of symptoms vary by study, pollen type, symptom, disease, and location but also sheds light on the complex interaction between environmental and biologic factors that affect pollen's role in allergic diseases and provide guidance on multiple areas for further investigation. Because of the importance of this information to patients who have this condition, it was chosen as the basis for this issue's “For the Patient” section entitled “Environmental Effects of Pollen on Allergic Disease.” This segment, found in the final pages of the print version of this issue and also available online, consists of a one-page article synopsis, written in a readily comprehensible fashion to help patients better understand the content of the full article.

Allergen-specific immunotherapy has been used for more than a century, and efforts to improve efficacy and reduce adverse effects have been continual. Among the modification of allergens and routes of treatment that have been studied is peptide immunotherapy. In this issue of the Proceedings, Midoro-Horiuti and Schein¹³ review the clinical studies of T-cell peptide immunotherapy for aeroallergens. The authors report that T-cell peptide immunotherapy failed to show clinical efficacy and was associated with adverse effects, and they theorize that these clinical outcomes were possibly attributable to the high effective rate of placebo and the development of IgE against T-cell epitope peptides.

In the third paper to address the importance of aeroallergens in respiratory disease, Peters et al.¹⁴ report on the efficacy of dupilumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) with and without allergic rhinitis. The authors performed a post hoc analysis of the efficacy and safety of dupilumab in patients with severe CRSwNP with/without coexisting AR in the pooled phase III SINUS-24/SINUS-52 studies. The authors found that dupilumab significantly improved objective and patient-reported measures of CRSwNP, including loss of smell, and reduced systemic and nasal biomarker levels versus placebo at week 24, with no significant treatment difference between patients with/without AR. Use of systemic corticosteroids and/or sinonasal surgery during treatment was significantly reduced with dupilumab versus placebo, irrespective of AR status. The authors conclude that, despite comorbid allergic rhinitis being commonly associated with poorer CRSwNP outcomes, dupilumab demonstrated significant improvements versus placebo in patients with severe CRSwNP irrespective of comorbid AR status.

Although real-world evidence studies have potential limitations (bias and confounding factors), their results may have broader generalizability than randomized controlled trial data and can provide insights into the effectiveness and safety of a drug during routine care. By using a retrospective cohort analysis of MarketScan (IBM Corporation, Somers, NY) administrative claims data, Riedl et al.¹⁵ investigated health-care utilization in patients with hereditary angioedema (HAE) treated with modern prophylactic HAE medicines (lanadelumab and subcutaneous C1-inhibitor concentrate). These investigators found that, although health-care resource utilization decreased after the initiation of treatment, angioedema-associated emergency department visits, hospitalizations, and on-demand treatment fills were not eliminated. These findings indicate ongoing disease and treatment burden despite the use of modern HAE medicines.

Although guidelines recommend that patients with anaphylaxis should be prescribed/carry epinephrine auto-injectors (EAI) and be referred to an allergist for further evaluation, barriers exist to implementing guideline recommendations. Acquisto et al.¹⁶ performed a retrospective, observational study of EAI prescribing in adult and pediatric patients after anaphylaxis presentation to the emergency department. Among 102 patients, 79% had an EAI prescribed (median cost $5), 71% filled their EAI prescription, 18% had a device change at dispensing, 23% received EAI training, and 22% had an allergist referral. The authors suggest that collaboration among emergency medicine clinicians, allergists, and pharmacists is needed to streamline treatment and follow-up.

The impact of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection or vaccination on disease control in patients with nonsteroidal anti-inflammatory drug–exacerbated respiratory disease is unknown. Cihanbeylerden et al.¹⁷ investigated this issue to determine whether patients experienced exacerbations of asthma or rhinitis after COVID-19 (coronavirus disease 2019) and evaluated their postvaccination asthma and rhinitis control data. Reassuringly, there was no deterioration in asthma and rhinitis control scores after SARS-CoV-2 vaccination, and there was no deterioration in the level of asthma control after COVID-19.

In summary, the collection of articles found within the pages of this issue provides further insight into the intersecting crossroads of inflammation and disease, which manifest as allergic, immunologic, and respiratory disorders that afflict patients whom the allergist/immunologist serves. They exemplify how the complexities of allergic disease pathogenesis and development continue to challenge the allergist/immunologist. In keeping with the overall mission of the Proceedings, which is to distribute timely information with regard to advancements in the knowledge and practice of allergy, asthma, and immunology to clinicians entrusted with the care of patients, we hope that the articles found within this issue will continue to foster enhanced patient management and outcomes. On behalf of the Editorial Board, we hope that you are able to make practical use of the diversity of literature offered in this issue of the Proceedings.