October 2024 ACIP Meeting Update: Influenza, COVID-19, RSV, and Other Vaccines

On September 20, 2024, the US Food and Drug Administration (FDA) approved live attenuated influenza vaccine (FluMist) for self or caregiver administration. For the current 2024–2025 influenza season, FluMist is available for administration by a health care provider only. It is anticipated that FluMist will be available for self or caregiver administration for the 2025–2026 influenza season. There will be presentations on this at future Advisory Committee on Immunization Practices (ACIP) meetings before the 2025–2026 season. During the June 2024 meeting, the ACIP voted to recommend high-dose inactivated (HD-IIV3) and adjuvanted inactivated (aIIV3) influenza vaccines as acceptable options for solid organ transplant (SOT) recipients aged 18 through 64 years, without a preference over other age-appropriate inactivated or recombinant vaccines. During the October meeting, a Vaccines for Children resolution was proposed and subsequently passed to add HD-IIV3 and aIIV3 options for vaccination coverage of 18-year-olds who are SOT recipients (Table 1). The Centers for Disease Control and Prevention (CDC) report showed that real-world vaccine effectiveness (VE) following receipt of any 2023–2024 seasonal influenza vaccine against any strain was 59% to 67% for outpatient settings and 52% to 61% for inpatient as of February 2024.¹ 

An update on highly pathogenic avian influenza A(H5N1) was presented by the CDC. Dairy cow illness was observed in early 2024, and as of October 18, 2024, it was confirmed in 324 US dairy herds across 14 states.

Human cases with dairy cattle and poultry exposures have been clinically mild, mainly eye symptoms only (conjunctivitis, eye discharge). Signs/symptoms may also include feeling feverish, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue, shortness of breath, or difficulty breathing. Less common symptoms include diarrhea, nausea, vomiting, or seizures. Although the current H5N1 clade remains in the “moderate” potential pandemic influenza risk category, the CDC’s current assessment is that the risk to the public from avian influenza A(H5N1) virus remains low and will continue to be monitored closely.

No official recommendations were made regarding human papillomavirus (HPV) vaccines during the October session. The primary goal of the session was to provide background information to frame future discussions revisiting the current recommended age range and schedule for HPV vaccination. The work group (WG) presented data on the efficacy of fewer doses of HPV and noted that in 2022, the World Health Organization made a recommendation for a 2-dose HPV vaccine schedule for those aged 9 years or older and, as an off-label option, a single-dose schedule for those aged 9 to 20 years. The current efforts of the WG are focused on data to inform policy on 2 potential considerations: a 2-dose schedule for persons aged 15 years and older and a one-dose schedule for persons aged 9 to 14 years. In addition, the WG is assessing a change to the current ACIP age recommendation, from “routinely recommended at age 11 to 12 years (can start at age 9 years)” to “routinely recommended at age 9 to 12 years” to allow more flexibility (and similar to current American Academy of Pediatrics [AAP] recommendations). The WG anticipates returning to the February 2025 meeting with additional data and partial Evidence to Recommendations (EtR) with a subsequent ACIP vote at a future meeting.

The maternal/pediatric respiratory syncytial virus (RSV) WG presented clinical trial data on a new RSV monoclonal antibody, clesrovimab, and reviewed a Vaccine Safety Datalink report on the incidence of preterm and small-for-gestational-age (SGA) birth following maternal immunization with RSV Pre-Fusion F protein (PreF) vaccines during pregnancy.

Clesrovimab, produced by Merck, is a human monoclonal for Pre F protein, which binds with high affinity to site IV of the RSV F protein, different than the site of action of nirsevimab, preventing fusion of the virus to host cells and blocking viral entry. Other features of clesrovimab include an extended half-life (45 days), compared with ∼69 days for nirsevimab, and high distribution to nasal tissues.^2,3 The proposed indication is for the prevention of RSV lower respiratory tract infection (LRTI) in neonates or infants born during or entering their first RSV season. Clesrovimab is given as a single intramuscular injection, with a fixed dose for all infants, regardless of weight. The sponsor shared data from their 2 pivotal trials: the completed “Protocol 004,” which was a phase 2b/3, randomized, placebo-controlled, blinded trial of the safety and efficacy of clesrovimab in healthy preterm and term infants through 6 months; and “Protocol 007,” an ongoing phase 3, randomized, palivizumab-controlled, partially blinded trial to evaluate the safety, efficacy and pharmacokinetics of clesrovimab for at-risk infants over 2 RSV seasons.

In Protocol 004 (NCT04767373), 3641 neonates and infants were randomized to receive either clesrovimab or saline placebo and then followed for 6 months. The primary endpoints were incidence of medically attended lower respiratory tract infection (MALRI) with at least 1 indicator of severity at 5 months post dose and incidence of adverse events; other endpoints included all-cause hospitalization, hospitalization for LRTI, severe MALRI, and acute respiratory tract infection. Study groups were balanced demographically, and it is worth noting that 631 infants (∼7%) were preterm infants born at 29 to 35 weeks gestational age. Efficacy was highest against severe MALRI and hospitalization for LRTI, at 90% to 92%, and 60.4% against the primary endpoint of medically attended lower respiratory tract infection. Approximately 75% of infants in both clesrovimab and placebo groups experienced at least 1 adverse event, with about 25% of those being considered drug related; the most frequently reported events were irritability (18.7% vs 19.7%) and somnolence (12.6% vs 14.2%) and fever (temperature >100.4°F), which occurred in ∼4% of both study groups. Serious adverse events were reported in 11.5% and 12.4% of clesrovimab and placebo groups, respectively. There were 10 deaths total (7 clesrovimab, 3 placebo) and none was considered drug related.

Protocol 007 (NCT04938830) was a safety study comparing the safety profiles of clesrovimab and palivizumab in infants at increased risk for RSV. This study enrolled 896 infants who were randomized to receive either 1 dose of clesrovimab or 3 to 5 doses of palivizumab during their first RSV season. Infants were then followed for 6 months, with the primary endpoint being the incidence of adverse events in the 42 days after receipt of a dose of clesrovimab or palivizumab. Both groups were balanced in terms of underlying medical conditions and age, with 45% of all subjects meeting AAP criteria for palivizumab use (preterm birth, congenital heart disease, or chronic lung disease). During the first RSV season, infants receiving clesrovimab and palivizumab experienced a similar proportion of adverse events, less than 30% of which were attributable to drug reactions, and the majority of which were mild or moderate. There were 12 deaths (8 in clesrovimab and 4 in palivizumab) but none of the deaths was considered related to the study interventions. Efficacy was a secondary endpoint for the first RSV season, and as such, incidence of MALRI and hospitalization were described for each group and were found to be similar. “Bridging” pharmacokinetic (PK) data were collected from the infants in Protocol 007 and compared with PK data from the main efficacy study, Protocol 004. These data support the extrapolation of efficacy from data on healthy infants to those at increased risk of severe disease. The WG felt that the efficacy and safety data presented at this meeting look promising, but they have also asked for additional PK, efficacy, and safety data from the sponsor. The half-life of clesrovimab is shorter than that of nirsevimab (42 vs 71 days) but the duration and level of efficacy appear to be similar based on these trials. They also noted weaknesses of these trials, including the timing of the trials, which were conducted in 2021, when typical rates and seasonality of RSV were altered as a result of the COVID-19 pandemic. The WG will review the additional data requested by the sponsor with plans to present the Grading of Recommendations Assessment Development and Evaluation (GRADE) analysis and EtR framework at the February 2025 ACIP meeting,

In an effort to further examine the risks of preterm birth (<37 weeks) and SGA infants (<10th percentile) observed in prelicensure trials of the maternal RSV PreF vaccines, a gestational age-matched cohort analysis (vaccinated vs unvaccinated) was performed on Vaccine Safety Datalink data for the 2023–2024 RSV season. Pregnant women who received RSV PreF vaccine between 30 and 36 weeks were matched at the time of vaccination to unvaccinated pregnant women who were at the same gestational age of their pregnancy and birth outcomes (incidence of birth before 37 weeks and infants who were SGA) were compared. Over 14 000 matched pairs were analyzed. The risk ratio for preterm birth was 0.90 (95% CI 0.80, 1.00), and for SGA infants was 1.02 (95% CI 0.93, 1.13) in RSV-vaccinated women compared with gestational age-matched unvaccinated controls. In summary, these data indicate that there is no increased risk for preterm birth or SGA infants following maternal immunization with RSV PreF vaccine. A similar analysis of additional safety endpoints, including stillbirth and maternal hypertensive disorders (preeclampsia, hemolysis, elevated enzymes, and low platelets syndrome (HELLP)), which have been associated with maternal RSV vaccination (Abrysvo specifically) in at least one other study, is ongoing. No recommendations were made at this meeting, with anticipation of further data available for review at the February 2025 meeting.

The meningococcal session covered 2 primary items, with a note made that the WG will be revisiting the entire adolescent meningococcal vaccine schedule in 2025. This session primarily reviewed changes to serogroup B meningococcal vaccine (MenB)-4C (Bexsero) FDA-approved interval and dosing as well as an analysis of GlaxoSmithKline’s (GSK) 2-dose pentavalent meningococcal conjugate vaccine (MenABCWY) that is anticipated to have a regulatory decision on February 14, 2025. A subsequent vote on the GSK pentavalent vaccine is anticipated at the February 2025 ACIP meeting. The session introduction included a note from the WG chair that current meningococcal disease incidence is 0.13 cases/100 000 population ( ∼1/million persons) in the United States and meningococcal serogroup B incidence is ∼0.02 cases/100 000 population ( ∼1 case per 5 000 000) while also noting that invasive meningococcal disease does have high associated morbidity and mortality.

To frame the complexities of the GSK’s pentavalent vaccine discussion, the WG reminded the group that the current strategy for meningococcal vaccination including MenB when indicated is:

• One quadrivalent (Q) MenACWY dose when aged 11 to 12 years and a booster when aged 16 years

• Two MenB doses (B) when aged 16 to 23 years (shared clinical decision-making); the preferred age range is aged 16 to 18 years.

This strategy is the baseline case and is referred to as Q-QB-B, reflecting a total of 4 meningococcal immunizations. Pentavalent vaccine (P) integration strategies consist of Q-P-B, P-P, or Q-P-P and these are the same strategies evaluated by the WG for the Pfizer (Penbraya) MenABCWY vote in October 2023.

There were 3 policy questions discussed, all of which included cumulative cost, cost-effectiveness, and cost per quality-adjusted life year (QALY) gained for each vaccination strategy vs no vaccination and the WG ultimately proposed the following:

• Patient/population, intervention, comparison and outcomes (PICO) 1: Should the pentavalent vaccine (P, MenABCWY) be included as an option for MenACWY/MenB vaccination in people currently recommended to receive both vaccines at the same visit? This is known as Q-P-B, potentially replacing the QB in the Q-QB-B current schedule with one P. See Table 2.

Several WG members noted that it would be important to harmonize recommendations between the GSK and Pfizer pentavalent vaccines unless there is a vaccine-specific reason to have a different recommendation. Recommendations for the use of both pentavalent vaccines could then be revisited as part of future adolescent schedule deliberations.

Given the recent FDA-approved MenB-4C (Bexsero) label change, ACIP reviewed the data and considered updated recommendations. The vaccine was initially licensed by the FDA under an accelerated approval process. New immunogenicity data supports changes to the dosing schedule to align with MenB-FHbp (Trumemba). Seroreponses measured by the 4-fold rise in serum bactericidal activity using human complement (hSBA) titers to each indicator MenB antigen showed a consistent trend of improved response with the 0, 6-month, and 0-, 2-, and 6-month intervals compared with the current 0 and 2 months. Following the EtR data review, the ACIP recommended MenB-4C be administered on a 0 and 6-month dosing interval vs a 0 and at least 1-month dosing interval, for the prevention of invasive meningococcal disease for persons aged 16 to 23 years recommended for MenB vaccination based on shared clinical decision-making. It also recommends MenB-4C be administered on a 0, 1 to 2, 6-month schedule, vs a 0 and at least 1-month schedule, for the prevention of invasive meningococcal disease among persons with persistent complement component deficiencies, those with complement inhibitor use, functional or anatomic asplenia, microbiologists routinely exposed to Neisseria meningitidis, or persons affected by an outbreak of serogroup B meningococcal disease. These recommendations harmonized with existing recommendations for MenB-FHbp and new dosing schedules are associated with increased immunogenicity compared with the previous schedule.

A new cytomegalovirus (CMV) vaccine WG is being convened because there are several candidate vaccines in development. Over the next 2 years, the new WG will review the epidemiology of CMV and congenital CMV and identify areas in which additional data are needed. It will review safety, immunogenicity, and efficacy data for CMV vaccine candidates. The WG will develop CMV vaccine policy options. The first WG meeting will be in November 2024, and the next presentation to ACIP will be at the February 2025 meeting, focusing on the burden of CMV and congenital CMV.

The mpox WG is reforming to review a National Institutes of Health study evaluating the use of a currently licensed mpox vaccine (JYNNEOS) in persons aged 12 to 17 years and to consider bringing to an ACIP vote the use of JYNNEOS in persons aged 12 to 17 years at risk for mpox during mpox outbreaks. It is anticipated that further discussion will be presented at the February 2025 ACIP meeting. The WG also is planning the publication of ACIP recommendations for persons aged 12 years and older in one consolidated morbidity and mortality weekly report (MMWR).

There is currently one licensed chikungunya vaccine (Ixchiq, manufactured by Valneva) in the United States for use as a single dose in persons aged at least 18 years; it is recommended for use in persons aged at least 18 years traveling to a country or territory where there is a chikungunya outbreak and laboratory workers with potential exposure to chikungunya virus. It is a live vaccine and as such is contraindicated in individuals with immunocompromising conditions. Data from a recently completed study in 12- to 17-year-olds are expected to be submitted to the FDA by the end of 2024 and a clinical trial of Ixchiq in 1- to 11-year-old children is underway, as is an ongoing 10-year immune persistence study to evaluate for the need for booster doses.

A virus-like particle (VLP) based chikungunya vaccine is under development by Bavarian Nordic (BN) on the Accelerated Approval pathway, and the sponsor recently submitted a Biologics License Application to the FDA in mid-June 2024. The proposed indications for this vaccine include use in all individuals aged 12 years and older who are living in US territories with ongoing chikungunya circulation and travelers. Licensure for this vaccine is being reviewed under Priority Review and the target action date is February 2025. At this ACIP meeting, the sponsor, BN, presented safety and immunogenicity data from 3 phase 2 studies and 2 phase 3 clinical trials. Overall, the WG summarized that the chikungunya virus (CHIKV) VLP vaccine will offer an option to adolescents who are at risk of acquiring Chikungunya and it appears to be immunogenic and well tolerated, but there is no vaccine efficacy data, and the safety database is relatively small. Also, notably, it is difficult to compare the CHIKV VLP vaccine to the approved live virus Ixchiq vaccine, as the 2 use different assays for determining immunogenicity. The next steps for the WG will be to perform the GRADE analysis of the VLP vaccine at a future meeting. There were questions from the committee at large regarding the potential use of CHIKV VLP vaccine in pregnancy to prevent congenital disease and if developmental and reproductive toxicity (DART) data exists. Per BN, there are DART data in rabbits and rats and no concerns were identified.

At the June 2024 ACIP Meeting, the committee approved recommendations that all individuals aged 6 months or older receive at least one dose of the 2024–2025 COVID-19 vaccine. Previous CDC clinical considerations also allowed for the possibility of additional doses of the COVID-19 vaccine via shared decision-making in immunocompromised individuals but without specific recommendations. Rates of severe disease remain highest in immunocompromised adults, who represent 15.6% of all persons hospitalized for COVID-19, but account for 27% of COVID-19-related intensive care unit (ICU) admissions (vs 15% in immunocompetent individuals), 18% of intubations (vs 6%) and 15% of in-hospital deaths (vs 4%) in data from COVID-NET. These differences in severe COVID-19 outcomes were not seen in children with immunocompromising conditions; however, the sample size was much smaller and therefore less reliable. Adults aged over 65 years are also at increased risk of severe disease and complications from COVID-19. No permissive language for multiple doses of the COVID-19 vaccine for older adults has been provided in past years. The focus of the COVID-19 WG’s presentations was the risks, benefits, timing, and overall feasibility of administration of multiple doses of COVID-19 vaccine in these 2 populations (immunocompromised individuals of all ages and adults ≥65 years).

In addition to the previous recommendation for the 2024–2025 vaccine, the policy questions proposed by the WG to the ACIP for a vote were:

1. Should a second dose of the 2024–2025 COVID-19 vaccine be recommended for adults aged 65 years and older?

2. Should a second dose of the 2024–2025 COVID-19 vaccine be recommended for people aged 6 months and older who are moderately or severely immunocompromised?

3. Should additional doses (ie, 3 or more) of the 2024–2025 COVID-19 vaccine be recommended for people aged 6 months and older who are moderately or severely immunocompromised under shared clinical decision-making?

The WG reported vaccine coverage and effectiveness data for the 2023–2024 COVID-19 vaccine through June 2024 in adults aged 65 years and older, as well as for immunocompromised adults aged 18 years and older. Thirty-seven percent of older adults received at least 1 dose of the 2023–2024 COVID-19 vaccine, and vaccine coverage in immunocompromised adults (18+) with 2 doses was only ∼5%. VE for the 2023–2024 COVID-19 vaccine against hospitalization and critical illness was ∼50% for adults aged more than 18 years for the first 2 months after immunization but waned to 0 by 6 months, which is similar to previous COVID-19 vaccines. A similar antibody waning curve was seen in immunocompromised individuals. Importantly, VE against other critical outcomes, including thromboembolic events, ICU admission, and death, remained higher (40%–50%) in adults aged 65 years or more at as late as 5 months post dose. Epidemiologic data continue to demonstrate twice yearly peaks of COVID-19 cases for the past 4 years, once in December through February and again in late summer (July-September), which suggests waning of natural immunity at 6 months postinfection, similar to what is seen with vaccination. These immunologic and epidemiologic data support a recommended 6-month interval for COVID-19 vaccination in those at highest risk of severe outcomes, including adults aged 65 years or more and immunocompromised individuals. The WG also discussed a minimum interval for repeat doses of the COVID-19 vaccine of 2 months in the setting of shared decision-making with their physician, which would allow flexibility for high-risk immunocompromised to time “booster” doses around major life or medical events (eg, pretransplant or planned immunosuppressive therapy).

The 3 policy question recommendations regarding repeat doses of the 2024–2025 COVID-19 vaccine for adults aged 65 years or more and immunocompromised individuals, as described above and in summary Table 1, were passed unanimously (15–0). The WG also provided additional clinical considerations for children aged 6 months through 4 years who are moderately to severely immunocompromised, emphasizing that these children should still receive the initial 2 (Moderna) or 3 (Pfizer) dose mRNA vaccine series, that at least one of those doses should be with the 2024–2025 formulation, and that an additional dose should be given 6 months after completion of the initial series.

A 21-valent pneumococcal conjugate vaccine was approved by the FDA for adults aged at least 18 years old on June 17, 2024. The WG emphasized that PCV21 is not simply a 20-valent pneumococcal conjugate vaccine (PCV20) with one additional serotype, it is a unique vaccine that targets serotypes that commonly cause disease in adults. The manufacturer currently does not have plans to seek an indication for routine PCV21 use in infants but will seek an indication for the use of PCV21 in children aged 2 to 18 years with a high-risk condition, with a phase 3 trial currently in progress. At the June 2024 ACIP meeting, the full committee requested that the WG present a summary of data on whether age-based recommendations for pneumococcal vaccines should be lowered to persons aged at least 50 years for all pneumococcal conjugate vaccines (PCVs). Data presented showed that PCV21 provides protection against an additional 31% of the invasive pneumococcal disease (IPD) serotypes in those 65 years and older and against 23% of the IPD serotypes in 19- to 64-year-olds compared with PCV20 alone.

After discussion, the WG settled on the following recommendations:

1. Lower the age-based recommendation for all PCVs aged to at least 50 years; the majority supported this option after a targeted discussion of the policy question.

2. Future booster doses may be needed to avoid increased pneumococcal disease burden in older adults; this likely will be in persons aged 65 years, but more data are necessary before this can be fully assessed.

Key uncertainties remain, the duration of protection following adult vaccination and the impact of new higher-valency vaccines currently in development.

Factors supporting lowering the PCV age-based recommendation to those aged at least 50 years include the relatively high burden of pneumococcal disease in adults aged 50 to 64 years, particularly among those with high-risk conditions, the potential for improved vaccine uptake through an age-based recommendation, and the potential to reduce pneumococcal disease incidence in demographic groups experiencing the highest burden. After a discussion of the factors above and available data, the ACIP voted to recommend a PCV for all PCV-naïve adults aged at least 50 years.

As with prior October ACIP meetings, changes to the child/adolescent and adult immunization schedules were presented. These changes reflect existing ACIP recommendations approved by the CDC Director and not a new policy. Also discussed changes to the way these schedules are presented to clinicians, public health providers, and the general public, including wording and formatting changes to improve useability. These changes were approved by a vote of 15 in favor and 0 opposed.

ACIP

Advisory Committee on Immunization Practices

CDC

Centers for Disease Control and Prevention

RSV

respiratory syncytial virus

PCV20

20-valent pneumococcal conjugate vaccine

AAP

American Academy of Pediatrics

EtR

Evidence to Recommendations

US FDA

US Food and Drug Administration

LRTI

lower respiratory tract infection

ICU

intensive care unit

GSK

GlaxoSmithKline

PCV20

20-valent pneumococcal conjugate vaccine

MenABCWY

pentavalent meningococcal conjugate vaccine

MenB

serogroup B meningococcal vaccine

VE

vaccine effectiveness

VLP

virus-like particle

VCR

vaccine research center

PreF

pre-fusion protein

GRADE

Grading of Recommendations Assessment Development and Evaluation

HELLP

hemolysis, elevated enzymes, and low platelets syndrome

QALY

quality-adjusted life year

PICO

patient/population, intervention, comparison and outcomes

hSBA

serum bactericidal activity using human complement

MMWR

morbidity and mortality weekly report

CHIKV

chikungunya virus