Lot-to-lot immunogenicity consistency of the respiratory syncytial virus prefusion F protein vaccine in older adults

Background Previous phase 3 studies showed that the AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) is well tolerated and efficacious in preventing RSV-associated lower respiratory tract disease in adults ≥ 60 years of age. This study evaluated lot-to-lot immunogenicity consistency, reactogenicity, and safety of three RSVPreF3 OA lots. Methods This phase 3, multicenter, double-blind study randomized (1:1:1) participants ≥ 60 years of age to receive one of three RSVPreF3 OA lots. Serum RSVPreF3-binding immunoglobulin G (IgG) concentration was assessed at baseline and 30 days post-vaccination. Lot-to-lot consistency was demonstrated if the two-sided 95 % confidence intervals (CIs) of the RSVPreF3-binding IgG geometric mean concentration (GMC) ratios between each lot pair at 30 days post-vaccination were within 0.67 and 1.50. Solicited adverse events (AEs) within four days, unsolicited AEs within 30 days, and serious AEs (SAEs) and potential immune-mediated diseases within six months post-vaccination were recorded. Results A total of 757 participants received RSVPreF3 OA, of whom 708 were included in the per-protocol set (234, 237, and 237 participants for each lot). Lot-to-lot consistency was demonstrated: GMC ratios were 1.06 (95 % CI: 0.94–1.21), 0.92 (0.81–1.04), and 0.87 (0.77–0.99) between the lot pairs (lot 1/2; 1/3; 2/3). For the three lots, the RSVPreF3-binding IgG concentration increased 11.84-, 11.29-, and 12.46-fold post-vaccination compared to baseline. The reporting rates of solicited and unsolicited AEs, SAEs, and potential immune-mediated diseases were balanced between lots. Twenty-one participants reported SAEs; one of these–a case of atrial fibrillation–was considered by the investigator as vaccine-related. SAEs with a fatal outcome were reported for four participants, none of which were considered by the investigator as vaccine-related. Conclusion This study demonstrated lot-to-lot immunogenicity consistency of three RSVPreF3 OA vaccine lots and indicated that the vaccine had an acceptable safety profile. ClinicalTrials.gov: NCT05059301.


Inclusion criteria
• Participants who, in the opinion of the investigator, could and would comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visit, ability to access and use a phone or other electronic communications).
Note: In case of physical incapacity that would preclude the self-completion of the diary cards, either site staff could assist the participant (for activities performed during site visits) or the participant could assign a caregiver to assist him/her with this activity (for activities performed at home).However, at no time could the site staff or caregiver evaluate the participant's health status while answering diaries or make decisions on behalf of the participant.
• A male or female aged ≥60 years at the time of first study intervention administration.
• Participants living in the general community or in an assisted living facility that provided minimal assistance, such that the participant was primarily responsible for self-care and activities of daily living.
• Written or witnessed informed consent obtained from the participant prior to performance of any study-specific procedure.
• Participants who were medically stable in the opinion of the investigator at the time of vaccination.Participants with chronic stable medical conditions with or without specific treatment, such as diabetes, hypertension, or cardiac disease, could participate in this study if considered by the investigator as medically stable.

Medical conditions
• Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., current malignancy, human immunodeficiency virus) or immunosuppressive/cytotoxic therapy (e.g., medication used during cancer chemotherapy, organ transplantation, or to treat autoimmune disorders), based on medical history and physical examination (no laboratory testing required).
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention(s).
• Serious or unstable chronic illness.
• Any history of dementia or any medical condition that moderately or severely impairs • Recurrent or uncontrolled neurological disorders or seizures.Participants with medically controlled active or chronic neurological diseases could be enrolled in the study as per investigator assessment, provided that their condition would allow them to comply with the requirements of the protocol (e.g., completion of the diary cards, attend phone call/study site visits).
• Significant underlying illness that in the opinion of the investigator would be expected to prevent completion of the study (e.g., life-threatening disease likely to limit survival up to study end [i.e., six months post-vaccination]).
• Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
Prior/concomitant therapy • Use of any investigational or non-registered product (drug, vaccine, or medical device) other than the study intervention(s) during the period beginning 30 days before study intervention administration and ending 30 days after study intervention administration, or planned use during the study period.
• Planned or actual administration of a vaccine not foreseen by the study protocol in the period starting 30 days before and ending 30 days after the study intervention administration, with the exception of inactivated and subunit influenza vaccines, which could be administered up to 14 days before or from 14 days after the study vaccination.
Note: In case an emergency mass vaccination for an unforeseen public health threat (e.g., a pandemic) was recommended and/or organized by the public health authorities, outside the routine immunization program, the time period described above could be reduced if necessary for that vaccine provided it was used according to the local governmental recommendations and that the Sponsor was notified accordingly.
• Previous vaccination with a respiratory syncytial virus (RSV) vaccine.
• Administration of long-acting immune-modifying drugs or planned administration at any time during the study period (e.g., infliximab).
• Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 90 days before the administration of the study intervention or planned administration during the study period.
• 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 study intervention administration or planned administration during the study period.For corticosteroids, this meant prednisone ≥20 mg/day or equivalent.Inhaled and topical steroids were allowed.
Prior/concurrent clinical study experience • Concurrently participating in another clinical study, at any time during the study period, in which the participant had been or would be exposed to an investigational or a noninvestigational vaccine/product (drug or invasive medical device).

Other exclusions
• History of chronic alcohol consumption and/or drug abuse as deemed by the investigator to render the potential participant unable/unlikely to provide accurate safety reports or comply with study procedures.
• Planned move during the study period that would prohibit participating in the study until study end.
• Participation of any study personnel or their immediate dependents, family, or household members.

Study design
Participants were enrolled with a balance between males and females, and in three age categories reflecting the age distribution in the general population, with approximately 40% of participants aged 60-69 years, 30% 70-79 years, and 10% ≥80 years.The remaining 20% were distributed freely across the age categories.

Randomization
Participants were randomized using an automated internet-based system, with a minimization method that accounted for age category (60-69 years, 70-79 years, and ≥80 years) and study center.Supplies were randomized within blocks for the different study centers, using the MATerial Excellence program, a program developed by GSK for use in SAS (Cary, NC, United States).

Intensity grading of solicited and unsolicited adverse events
All solicited and unsolicited AEs were graded as either 1 (mild), 2 (moderate), or 3 (severe).

Event Grade Parameter
Administration-site solicited AE  N, number of participants with solicited safety data available; AE, adverse event; n/%, number/percentage of participants in a given category; CI, confidence interval.
deemed necessary for clinical evaluation, the investigator could use tools such as Mini Mental State Exam, Mini Cog or Montreal Cognitive Assessment to determine cognition levels of the participant.