Indications

Based on clinical trials and safety data, the respiratory syncytial virus prefusion F (RSVPreF3) vaccine has received initial approval from the U.S. Food and Drug Administration (FDA) for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV) in adults aged 60 and older. RSV poses a significant risk to this age group, leading to acute respiratory infection, LRTD, clinical complications, and even death.[1] 

FDA Approval

FDA approved the RSVPreF3 vaccine on May 3, 2023, to prevent RSV-induced LRTD in individuals aged 60 and older in the United States. The approval was based on data derived from a randomized, placebo-controlled phase III trial (AReSVi-006), which enrolled 24,966 participants across 17 countries.[1] The pivotal trial demonstrated that the vaccine 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), successfully meeting the primary endpoint.[1]

Moreover, the 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).[1] 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.[1] Notably, the incidences of serious adverse events and potential immune-mediated diseases were comparable between the vaccine and placebo groups.[1]

Background Information on Discovery and Development

RSV is a common respiratory pathogen belonging to the Paramyxoviridae family. This enveloped virus possesses a single-stranded RNA genome.[2] 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.[2]

Common signs and symptoms of RSV infection include a runny nose, coughing, sneezing, fever, decreased appetite, irritability, wheezing or difficulty breathing, rapid or labored breathing, and cyanosis. RSV infection can result in various complications, including bronchiolitis, pneumonia, and respiratory failure.[3]

The RSVPreF3 vaccine is developed as a recombinant subunit vaccine, comprising a prefusion form (pre-F) of the RSV F glycoprotein antigen (RSVPreF3) combined with GSK's proprietary AS01 adjuvant. The AS01 adjuvant incorporates QS-21 Stimulon, MPL, and liposomes, enhancing the immune response to the vaccine.[4] The prefusion form of the RSV F protein exhibits higher immunogenicity and neutralizing activity than the postfusion form, eliciting high titers of neutralizing antibodies against both RSV A and B subtypes.[5] The AS01 adjuvant enhances the immune response and helps overcome the natural decline in immunity associated with aging.[4] 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.[6]

The development of RSVPreF3 is based on extensive research on the structure and behavior of the RSV virus. The primary focus of this vaccine is the F protein, a prominent surface protein of the RSV virus. The F protein plays a critical role in facilitating viral fusion and entry into host cells.[7] Researchers have discovered that the F protein's prefusion (pre-F) form is particularly adept at inducing a strong and effective immune response than the postfusion form.[2] 

Clinical studies assessed the immune response elicited by the vaccine, its safety profile, and its effectiveness in preventing RSV infection within the target populations. 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 vaccine's immunogenicity, safety, and ability to prevent RSV-related illnesses. The FDA meticulously reviewed the data to ensure RSVPreF3 exhibited adequate efficacy and a satisfactory safety profile for its intended use.

Mechanism of Action

RSVPreF3 is a novel vaccine that effectively stimulates immune response and provides immunity against RSV through specific mechanisms of action, as listed below.

1. Targeting the pre-F form of the F protein: The RSVPreF3 vaccine is formulated to specifically target the pre-F form of the F protein present on the surface of the RSV virus. This protein is pivotal in viral fusion and facilitates the entry of the virus into the host cells. By focusing on this critical viral protein, the vaccine aims to interrupt the infection process by targeting the pre-F form of the F protein.[8]

2. Induction of neutralizing antibodies: RSVPreF3 stimulates the production of neutralizing antibodies specifically targeting the pre-F protein by triggering the immune system. These antibodies bind to the pre-F protein located on the surface of the RSV virus, preventing its attachment to and entry into host cells. As a result, virus neutralization occurs, significantly lowering the risk of infection and subsequent viral replication.[9]

3. Stimulation of humoral immune response: The vaccine induces a robust humoral immune response characterized by the production of specific antibodies, particularly immunoglobulin G (IgG) antibodies. These antibodies recognize and bind to the pre-F protein, blocking viral attachment and fusion with host cells.[10] The humoral immune response is essential for preventing RSV infection and mitigating the severity of associated symptoms. In addition, the vaccine facilitates the transplacental transfer of maternal antibodies to infants, providing passive protection against RSV infection during early life.

4. Activation of the cellular immune response: The RSVPreF3 vaccine triggers the activation of the cellular immune response by stimulating polyfunctional CD4+ T cells that express multiple cytokines, such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). These T cells also exhibit cytotoxicity markers, including CD40 ligand (CD40L) and CD107a. CD4+ T cells help coordinate the immune response, assist B cells in antibody production, and activate other immune cells. On the other hand, CD8+ T cells can directly target and eliminate infected cells, thereby restricting intracellular viral replication.[11]

5. Memory B-cell and T-cell formation: RSVPreF3 promotes the development of memory B and T cells, which are integral to the immune system's long-term memory. 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. This immune memory provides long-term protection against RSV infection and contributes to the prevention of severe illness.[12]

In summary, the RSVPreF3 vaccine employs a multifaceted approach to enhance immune responses against RSV. By specifically targeting the pre-F protein, the RSVPreF3 vaccine stimulates the production of neutralizing antibodies, activates both humoral and cellular immune responses, and fosters the development of memory B and T cells. This comprehensive strategy effectively strengthens the immune system's ability to recognize and eliminate RSV, thereby offering significant protection against RSV infection.[13]

Immune Response Kinetics

As an mRNA vaccine, RSVPreF3 does not adhere to traditional pharmacokinetic principles observed in small-molecule drugs.[2] Upon administration, RSVPreF3 is taken up by antigen-presenting cells, primarily dendritic cells, located at the injection site. These cells process the vaccine antigens, presenting them to the immune system to initiate an immune response. The duration of immune protection conferred by RSVPreF3 can vary among individuals. Although the initial immune response develops within weeks after vaccination, the persistence of vaccine-induced immunity can range from months to years. However, the precise duration and level of protection may be influenced by an individual's immune status, age, and the potential for gradual waning of immunity over time.

The AS01 adjuvant 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).[4] 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.[4] 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.[4]

Administration

The RSVPreF3 vaccine is offered in a parenteral dosage form, specifically as a lyophilized antigen powder component provided in a single-dose vial. The vaccine is prepared by reconstituting it with the accompanying vial of adjuvant suspension. Before reconstitution, both the vial containing the lyophilized powder component and the vial with the adjuvant should be stored in a refrigerator and maintained between 2 and 8 °C (36-46 °F) in their original packaging to shield them from light. Once reconstituted, the vaccine should continue to be stored between 2 and 8 °C. The vaccine must be protected from light and utilized within 4 hours if stored at room temperature.

Available dosage form: Intramuscular injection

Strength: Each dose contains 120 μg of RSVPreF3 adjuvanted with AS01E.

Adult dose: A single dose of 0.5 mL is recommended for adults after reconstitution. 

Specific Patient Population

The administration of RSVPreF3 may require specific considerations for certain populations. Some important points regarding the administration of RSVPreF3 in specific populations are listed below.

Considerations in older patients: RSVPreF3 is indicated explicitly for preventing RSV infection in individuals aged 60 and older. The FDA has approved RSVPreF3 for use in older patients with a heightened risk of experiencing severe RSV-associated respiratory illness.[14] The vaccine can be administered to older adults following the standard dosage and administration guidelines.

Considerations in children: The use of the RSVPreF3 vaccine in the pediatric population has not received FDA approval yet. Clinical trials are underway to assess the safety and efficacy of the vaccine in children and infants. 

Considerations in pregnant women: The use of the RSVPreF3 vaccine in pregnant women has not yet been approved by the FDA. However, some clinical trials have proven the vaccine's effectiveness in this population. Results indicate that pregnant women between 24 and 36 weeks of gestation can receive the vaccine as part of a maternal immunization program to protect their infants against RSV infection in early life.[6] The recommended dose during pregnancy is a single dose of either 120 or 240 μg of RSVPreF3 antigen, with or without aluminum hydroxide adjuvant.

Adverse Effects

The adverse effects of the RSVPreF3 vaccine have undergone evaluation through numerous clinical trials involving diverse populations, including non-pregnant women, pregnant women, and older adults.[1][15]

• Local reactions at the injection site: Local reactions at the injection site are commonly reported as adverse effects of RSVPreF3. Typically, these reactions are mild to moderate in nature and may manifest as pain, tenderness, swelling, redness, or itching at the injection site. Pain is the most common local reaction experienced among approximately 60% to 80% of vaccine recipients.[6] Fortunately, these local reactions tend to resolve spontaneously within a few days without specific treatment.

• Systemic reactions: Some individuals may experience systemic reactions following RSVPreF3 vaccination, but they 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 20% to 40% of vaccine recipients.[1] These symptoms are typically self-limiting and resolve within a short period.

• Allergic reactions: Although rare, allergic reactions following RSVPreF3 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.

Overall, administering the RSVPreF3 vaccine does not increase the risk of serious adverse events compared to the placebo within any population. The incidences of serious adverse events in both the vaccine and placebo groups are similar, ranging from 1% to 5%.[1] Furthermore, the RSVPreF3 vaccine does not elevate the risk of potential immune-mediated diseases, such as Guillain–Barré syndrome, rheumatoid arthritis, or inflammatory bowel disease, compared to the placebo in any population.[1]

Drug Interactions

As an mRNA vaccine, RSVPreF3 is not typically associated with significant drug-drug interactions. Vaccines such as RSVPreF3 primarily interact with the immune system to induce an immune response and offer protection against specific diseases. However, some general considerations regarding drug-drug interactions with RSVPreF3 are listed below.

Immunosuppressive medications: Individuals undergoing immunosuppressive therapies, such as corticosteroids, chemotherapy, or immunomodulatory agents, may experience a reduced immune response to RSVPreF3. These medications can weaken the immune system's ability to react to the vaccine. Therefore, as a precautionary measure, it is recommended to administer the RSVPreF3 vaccine at least 2 weeks before or after receiving immunosuppressive therapy, if possible.[16]

Other vaccines: The concomitant administration of RSVPreF3 with other vaccines is generally acceptable. However, the clinical team must adhere to the recommended vaccination schedule and guidelines for each vaccine. Certain vaccines may require specific intervals between administrations or separate injection sites to minimize the potential for interference or local reactions.[16]

Contraindications

RSVPreF3 should not be administered to individuals with a history of severe allergic reactions, including anaphylaxis. Furthermore, individuals who have previously experienced a severe or life-threatening reaction to the same vaccine or a vaccine containing similar components may be contraindicated from receiving RSVPreF3.[12] This contraindication extends to those who have had a severe reaction following a previous dose of the vaccine.

In certain instances, vaccines may be contraindicated or necessitate careful consideration for individuals with significantly compromised immune systems, such as those undergoing chemotherapy or receiving immunosuppressive therapies. These individuals may experience a diminished immune response to the vaccine.[7] Healthcare providers will assess the risks and benefits of vaccination on a case-by-case basis in immunocompromised individuals.

Box warning: No specific boxed warnings have been issued by the FDA for RSVPreF3. However, all clinical staff must remain vigilant, as drug safety information can evolve and change over time.

Monitoring

Following the administration of RSVPreF3, a comprehensive safety monitoring process is implemented to assess and evaluate the occurrence of any adverse effects.[17] Healthcare providers and vaccine manufacturers actively participate in post-marketing surveillance programs designed to monitor the safety profile of RSVPreF3 in real-world settings. This ongoing monitoring is essential in detecting and identifying rare or long-term adverse effects that may not have been observed during clinical trials.

Toxicity

RSVPreF3 is generally well tolerated and exhibits a favorable safety profile.[1] However, as with any medication or vaccine, there is a potential toxicity or adverse effects risk.

Enhancing Healthcare Team Outcomes

The administration of RSVPreF3 necessitates interdisciplinary collaboration and effective communication among healthcare professionals to ensure the safe and efficient administration of the vaccine. Some critical aspects of interprofessional collaboration and communication in RSVPreF3 administration are listed below.

Vaccine education and training: Healthcare professionals across various disciplines, such as physicians, nurses, pharmacists, and allied health personnel, should receive comprehensive education and training on RSVPreF3. This education should comprehensively help clinicians understand the vaccine's indications, contraindications, dosage, administration technique, potential adverse effects, and safety considerations. 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.

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 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 the decision-making process.

Vaccine administration protocols: Interdisciplinary collaboration is essential in developing standardized protocols for administering the RSVPreF3 vaccine. 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 adverse events associated with the RSVPreF3 vaccine. 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.