Continuing Education Activity

Respiratory syncytial virus (RSV) is a prevalent respiratory pathogen that primarily affects infants, young children, older adults, and individuals with compromised immune systems. RSV is a significant cause of acute respiratory infection, lower respiratory tract disease (LRTD), clinical complications, and death in infants and older adults. The U.S. Food and Drug Administration (FDA) approved the first vaccines against RSV in 2023. The recombinant subunit RSV prefusion F3 (RSVPreF3) vaccine contains the RSV F glycoprotein stabilized in its prefusion (pre-F) state. By targeting the pre-F glycoprotein, the vaccine stimulates the production of neutralizing antibodies, activates both humoral and cellular immune responses, and promotes the formation of memory B and T cells. This activity provides comprehensive information on the indications, administration, dosage recommendations, mechanism of action, monitoring, adverse reactions, precautions, and contraindications associated with RSVPreF3 vaccines. This activity empowers healthcare teams to identify patients at high risk of severe RSV infection outcomes and to recommend and administer the RSVPreF3 vaccine according to nationally accepted guidelines.

Objectives:

• Identify appropriate candidates for the RSVPreF3 vaccine based on age, risk factors, and clinical guidelines.

• Screen patients for potential contraindications or precautions related to RSVPreF3 vaccination, considering their medical history, allergies, and current medications.

• Implement proper techniques for preparing, storing, handling, and administering the RSVPreF3 vaccine to maintain its potency and effectiveness.

• Collaborate with other healthcare professionals to effectively implement RSVPreF3 vaccination, including sharing information, monitoring vaccine coverage, addressing barriers, and integrating it into routine immunization schedules.

Indications

Vaccines against the respiratory syncytial virus (RSV) are indicated for adults aged 60 and older [1] and pregnant persons at 32 to 36 weeks gestation.[2] 

Background Information

RSV is a common respiratory pathogen belonging to the Paramyxoviridae family. This enveloped virus possesses a single-stranded negative-sense RNA genome.[3] This virus has a wide-ranging impact on different age groups, including infants, young children, older adults, and individuals with compromised immune systems. RSV has a characteristic fusion protein (F protein) on its surface, facilitating its entry into host cells. RSV is primarily transmitted through respiratory droplets, which are expelled when an infected person coughs or sneezes. This virus can also survive on surfaces and objects, allowing indirect transmission through contact when individuals touch a contaminated surface and subsequently touch their face. RSV is highly contagious, and close contact with an infected individual significantly increases the risk of transmission.[4]

Common signs and symptoms of RSV infection include a runny nose, coughing, sneezing, fever, decreased appetite, irritability, wheezing, rapid or labored breathing, and cyanosis. RSV infection can result in complications, including bronchiolitis, pneumonia, and respiratory failure.[4]

Both RSV vaccines approved for use in the US are protein-subunit vaccines containing the RSV F protein stabilized in its prefusion (pre-F) state.[5][6] Researchers have discovered that the F protein's pre-F form is particularly adept at inducing a stronger and more effective immune response than the postfusion form.[3] GSK's RSVPreF3 vaccine contains a liposome-based adjuvant to enhance the immune response to the vaccine, whereas Pfizer's RSVPreF vaccine is unadjuvanted.[5][6] 

FDA Approval

The U.S. Food and Drug Administration (FDA) approved the RSVPreF3 and RSVPreF vaccines in May 2023 for the prevention of RSV-induced lower respiratory tract disease (RSV-LRTD) in individuals aged 60 and older in the United States. The FDA approval process encompassed a comprehensive review of data obtained from preclinical studies, early-phase trials, and large-scale clinical trials. These studies thoroughly evaluated the vaccines' immunogenicity, safety, and ability to prevent RSV-related illnesses. The FDA meticulously reviewed the data to ensure that both vaccines exhibited adequate efficacy and a satisfactory safety profile for their intended uses.[1]

In August 2023, the FDA additionally approved the unadjuvanted RSVPreF vaccine for use in pregnant people between 32 and 36 weeks gestation.[2] The strategy of vaccinating pregnant people is based on the premise that the transplacental transfer of maternal vaccine-induced antibodies will provide passive protection to infants during the first few months of life.[7] Influenza and Tdap vaccines are both routinely administered to pregnant people for similar reasons.[8][9]

Clinical Trial Results

A randomized, placebo-controlled phase III trial of the adjuvanted RSVPreF3 vaccine (AReSVi-006), involving 24,966 participants across 17 countries, demonstrated that the immunization achieved an overall efficacy of 82.6% (96.95% CI, 57.9-94.1) against RSV-LRTD confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR) over a median follow-up period of 6.7 months, successfully meeting the primary endpoint.[5] Moreover, the adjuvanted vaccine effectively prevented severe RSV-LRTD (94.1%, 95% CI, 62.4-99.9) and RSV-related acute respiratory infection (71.7%, 95% CI, 56.2-82.3).[5] The vaccine's efficacy remained consistent across both RSV A and B subtypes, diverse age groups, and coexisting conditions. The vaccine demonstrated a higher reactogenicity than the placebo, although most adverse events reported were transient and of mild-to-moderate severity.[5] Notably, the incidences of serious adverse events and potential immune-mediated diseases were comparable between the vaccine and placebo groups.[5]

A multicenter phase III clinical trial of 34,284 participants (RENOIR) found similar results for the efficacy and safety of the unadjuvanted RSVPreF vaccine in adults aged 60 and older.[1] The incidence of local reactions was higher among RSVPreF vaccine recipients than among placebo groups, but the rates of systemic and severe adverse events were similar between vaccine and placebo groups.[6]

Extensive vaccine testing, including preclinical studies and phase I and II trials conducted on non-pregnant and pregnant women, demonstrated a favorable safety profile and robust immunogenicity.[10] A randomized, placebo-controlled phase III clinical trial involving 7,358 pregnant individuals between the 24th and 36th weeks of gestation (MATISSE) assessed RSVPreF vaccine efficacy in preventing medically attended RSV-LRTD among participants' infants during the first 90, 120, 150, and 180 days following birth.[7] The study found an 81.8% vaccine efficacy against severe RSV-LRTD within 90 days after birth (95% CI, 40.6-96.3) and 57.1% efficacy against RSV-LRTD of any severity within the same period (95% CI, 14.7-79.8). These efficacies dropped to 69.4% (95% CI, 44.3-84.1) and 51.3% (95% CI, 29.4-66.8), respectively, by 180 days after birth.[7] As with the 60 and older age cohort, the incidence of local reactions was higher among vaccine recipients than in the placebo group; however, rates of systemic and severe adverse events were similar in both groups. The incidence of adverse events occurring among infants within 1 month of birth was similar between the vaccine and placebo groups.[7]

Mechanism of Action

RSVPreF3 and RSVPreF vaccines stimulate the humoral and cellular immune responses and provide immunity against RSV by targeting the pre-F forms of the F proteins present on the surface of RSV subgroups A and B. The F protein is pivotal in viral fusion and facilitates the entry of the virus into the host cells.[11] 

The vaccines stimulate the production of neutralizing antibodies that recognize and bind to the pre-F protein, blocking viral attachment and fusion with host cells.[12] As a result, virus neutralization occurs, significantly lowering the risk of infection and subsequent viral replication.[13] In addition, the vaccine facilitates the transplacental transfer of maternal antibodies to infants, providing passive protection against RSV infection in the first 3-6 months of life.[7]

The RSVPreF3 and RSVPreF vaccines also activate the cellular immune response by stimulating polyfunctional CD4 T cells and memory B cells. These memory cells retain a "memory" of the RSV antigens encountered during vaccination, enabling a rapid and robust immune response upon subsequent exposure to RSV.[14]

The AS01 adjuvant contained in the RSVPreF3 vaccine is a liposomal formulation that combines 2 immunostimulants that are QS-21, extracted from the bark of the Quillaja saponaria tree, and MPL, a synthetic derivative of bacterial lipopolysaccharide (Salmonella Minnesota strain).[15] The AS01 adjuvant enhances the immune response to the RSVPreF3 antigen by activating innate immune cells, inducing cytokine production, promoting antigen presentation, and stimulating humoral and cellular immunity.[15] Moreover, the AS01 adjuvant also helps overcome the natural decline in immunity that accompanies aging by amplifying the magnitude and quality of the antibody response.[15]

Administration

Storage: Before reconstitution, both vaccines and their diluents should be stored in refrigerators and maintained between 2 and 8 °C (36-46 °F) in their original packaging to shield them from light. Once reconstituted, the vaccine should be administered immediately. If not administered immediately, the vaccine must be protected from light and either stored in the refrigerator or at room temperature. Discard any vaccine that is not used within 4 hours of reconstitution.

Preparation: Both vaccines are prepared by reconstitution. RSVPreF3 is reconstituted with the adjuvant solution, whereas RSVPreF is reconstituted with sterile water.[5][16] Use only the diluent supplied by the manufacturer.

Route: Intramuscular injection

Strength: Each dose contains 120 μg of vaccine. In addition, the adjuvanted RSVPreF3 vaccine contains 25 μg of QS-21 and 25 μg of MPL.[5]

Dose: A single dose of 0.5 mL is recommended for adults after reconstitution.[1][2]

Coadministration with other vaccines: Either RSVPreF3 or RSVPreF may be administered at the same visit with any other adult vaccine.[1][2]

Considerations for older adults: Either the adjuvanted RSVPreF3 or the unadjuvanted RSVPreF may be administered to adults aged 60 or older.[1] The U.S. Centers for Disease Control and Prevention (CDC) recommends that adults aged 60 years and older may receive RSV vaccination based on shared clinical decision-making between the clinician and patient. The decision whether to vaccinate should consider the patient's risks for severe RSV-LRTD, their preferences and values, and the clinician's discretion. Risk factors for severe RSV-LRTD include:[1]

• Chronic obstructive pulmonary disease
• Moderate or severe immunocompromise
• Congestive heart failure
• Stroke
• Hematologic disorders
• Chronic kidney disease
• Medical frailty
• Residence in a long-term care facility

Considerations for pregnant people: Only the unadjuvanted RSVPreF vaccine is currently indicated for vaccination of pregnant people.[2] The CDC recommends that pregnant people receive a one-time dose at 32-36 weeks gestation in September through January in the continental U.S. RSV season varies by climate, so clinicians practicing outside the continental U.S. should follow their local, state, or territorial guidance on optimal timing of vaccination. Currently, CDC guidance does not address whether patients should receive additional doses of the RSVPreF vaccine during subsequent pregnancies; the CDC may update its guidance in the future to address this scenario should additional data become available.[2]

Use of nirsevimab in infants following maternal RSVPreF vaccination: Nirsevimab is a long-acting monoclonal antibody against RSV for infants aged less than 8 months who are born during or entering their first RSV season and for infants and toddlers aged 8-19 months at high risk of severe RSV disease who are entering their second RSV season.[17] The CDC recommends either RSVPreF vaccination during pregnancy or nirsevimab administration to infants younger than 8 months, but not both.[2] Clinicians providing prenatal care to pregnant people during RSV season should discuss the advantages and disadvantages of RSVPreF vaccine and nirsevimab with their patients. However, infants and toddlers aged 8 to 19 months at high risk of severe RSV disease may still receive nirsevimab in their second RSV season regardless of whether their parent received RSVPreF during pregnancy.[2]

Adverse Effects

The adverse effects of the RSVPreF3 and RSVPreF vaccines have undergone evaluation through numerous clinical trials involving diverse populations, including non-pregnant women, pregnant women, and older adults.[5][6][7][18]

• Local reactions at the injection site: The adjuvanted RSVPreF3 vaccine is more reactogenic than the unadjuvanted RSVPreF vaccine, although local reactions at the injection site are commonly reported adverse effects of both vaccines.[1] Typically, these reactions are mild to moderate and may manifest as pain, tenderness, swelling, redness, or itching at the injection site. Pain is the most common local reaction to either vaccine, occurring among approximately 60% to 80% of RSVPreF3 vaccine recipients and 10% to 40% of RSVPreF vaccine recipients.[6][7][10] These local reactions typically resolve spontaneously within 1-2 days without specific treatment; however, 3.8% of RSVPreF3 vaccine recipients and 1.0% of RSVPreF vaccine recipients reported severe reactogenicity events during clinical trials.[1]

• Systemic reactions: Systemic reactions following RSVPreF3 or RSVPreF vaccination are generally mild and transient. Common systemic reactions may include fever, headache, fatigue, muscle pain, joint pain, chills, or general malaise. The most common systemic reactions are fatigue and headache experienced by approximately 25% to 35% of RSVPreF3 vaccine recipients and approximately 10% to 20% of RSVPreF vaccine recipients.[5][6] These symptoms are typically self-limiting and resolve within a short period.

• Serious adverse events: Overall, the rates of serious adverse events in the RSVPreF3 and RSVPre3 vaccine clinical trials were similar between the vaccine and placebo groups.[5][6][7] However, the FDA and CDC noted a small but statistically significant increase in atrial fibrillation among RSVPreF3 and RSVPreF vaccine recipients aged 60 years or older compared with placebo recipients in the same age group. Postmarketing studies and surveillance are ongoing to better evaluate the risk of atrial fibrillation after vaccination against RSV.[1]

• Allergic reactions: Although rare, allergic reactions following RSVPreF3 or RSVPreF vaccination may manifest as hives, itching, swelling of the face or throat, difficulty breathing, or wheezing. Although severe allergic reactions, known as anaphylaxis, are infrequent, they can potentially happen. Anaphylaxis is a severe, life-threatening allergic reaction characterized by difficulty breathing, rapid heartbeat, dizziness, and loss of consciousness. Immediate medical attention is required if anaphylaxis is suspected.

• Pregnancy complications: Infants whose parents received the RSVPreF vaccine during pregnancy had similar rates of prematurity, low birth rate, developmental delay, and other serious adverse events within 24 months of birth compared to those whose parents received a placebo. However, people with high-risk pregnancies were excluded from the clinical trials, so data is lacking on the risks of RSV vaccination in this group.[7] A small and statistically insignificant increase in preeclampsia was observed in the RSVPreF vaccine group (1.8%), compared with the placebo group (1.4%).[7] Postmarketing studies and surveillance are ongoing to better evaluate the risk of preeclampsia following RSVPreF vaccination during pregnancy.[1]

Contraindications

RSVPreF3 and RSVPreF vaccines should not be administered to individuals with a history of severe allergic reactions, including anaphylaxis, to any vaccine component.[1][2]

Precautions 

Acute illness: Vaccination should be temporarily delayed in persons experiencing moderate-to-severe acute illness until their illness has resolved or stabilized.[1] Vaccination does not need to be delayed in persons with mild or chronic illnesses.

Risk of preterm birth: The current data do not provide enough information to definitively confirm or rule out a cause-and-effect relationship between preterm birth and the use of RSVPreF. To mitigate any potential risk of preterm birth before 32 weeks of gestation, it is recommended to administer RSVPreF to pregnant individuals within the gestational age range of 32 to 36 weeks. Notably, pregnant individuals at an elevated risk of preterm birth were typically not included in clinical trials.[1]

Monitoring

The CDC conducts comprehensive vaccine safety monitoring to assess and evaluate the occurrence of any adverse effects, including cases of Guillain-Barré syndrome, preterm birth, hypertensive disorders of pregnancy, transverse myelitis, acute disseminated encephalomyelitis, and other inflammatory neurologic events after RSV vaccination.[1][2] This ongoing monitoring is essential in detecting and identifying rare or long-term adverse effects that may not have been observed during clinical trials. In accordance with FDA requirements, GSK will conduct a postmarketing study evaluating the risk of atrial fibrillation after receipt of the RSVPreF3 vaccine, and Pfizer will conduct postmarketing studies assessing the risks of atrial fibrillation, preterm birth, and hypertensive disorders of pregnancy following RSVPreF vaccination.[1][2]

US healthcare providers should report any clinically significant adverse events after vaccination to the Vaccine Adverse Events Reporting System (VAERS) at https://vaers.hhs.gov/index.html.[1]

Enhancing Healthcare Team Outcomes

RSVPreF3 and RSVPreF vaccines are important new tools to reduce morbidity and mortality caused by RSV among older adults and infants. Interdisciplinary collaboration and effective communication among healthcare professionals is critical to ensure the safe and efficient administration of these vaccines. 

Vaccine education and training: Healthcare professionals across various disciplines, including physicians, nurses, pharmacists, and allied health personnel, should receive comprehensive education and training on RSVPreF3 and RSVPreF vaccines. This education should comprehensively help clinicians understand the vaccines' indications, contraindications, dosage, administration technique, and potential adverse events. Regular updates on the most recent guidelines and recommendations should be provided to ensure all team members are well-informed and up-to-date with the latest information. Non-clinical staff should also be educated to ensure they provide consistent vaccine messaging to patients.[19]

Shared decision-making approach: Interdisciplinary collaboration includes engaging in shared decision-making with patients and their caregivers. Healthcare professionals should communicate the benefits, risks, and potential outcomes of RSVPreF3 and RSVPreF vaccination to patients and their family members. This collaborative approach fosters open dialogue, addresses concerns or questions, and ensures that patients and caregivers are actively involved in decision-making.[1]

Vaccine administration protocols: Interdisciplinary collaboration is essential in developing standardized protocols for administering the RSVPreF3 and RSVPreF vaccines. These protocols should include guidelines on the vaccine's proper storage, preparation, handling, and administration techniques. Clear communication channels should be established to ensure that all healthcare professionals involved in the administration process are well-informed and consistently adhere to these protocols.

Adverse event reporting: Interdisciplinary collaboration is crucial in monitoring and reporting vaccine adverse events. All healthcare professionals should be familiar with the established reporting mechanisms and promptly report any suspected adverse events to the appropriate regulatory authorities. By sharing this vital information, healthcare professionals enhance post-marketing surveillance and facilitate the ongoing evaluation of vaccine safety.