6.1 ACIP Adult Respiratory Vaccines: Influenza, COVID-19, RSV & Pneumococcal

Epidemiology and Burden of Vaccine-Preventable Adult Respiratory Diseases

Acute respiratory infections represent one of the leading causes of preventable adult morbidity, functional decline, hospitalization, and mortality in the United States. Four major respiratory pathogens—Influenza viruses (types A and B), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Respiratory Syncytial Virus (RSV), and Streptococcus pneumoniae (pneumococcus)—disproportionately afflict older adults (aged ≥ 65 years) and individuals with underlying chronic cardiopulmonary, renal, hepatic, or metabolic multimorbidity.

In older adults, the physiological process of immunosenescence—characterized by thymic involution, reduced naive T-cell diversity, blunted germinal center responses, and impaired plasma cell antibody affinity maturation—substantially weakens host defense against respiratory pathogens. Consequently, infection frequently triggers catastrophic cascades, including acute exacerbations of heart failure, chronic obstructive pulmonary disease (COPD) decompensation, secondary bacterial superinfections, acute kidney injury, and accelerated functional disability. Maintaining comprehensive, up-to-date knowledge of the Advisory Committee on Immunization Practices (ACIP) adult immunization schedule is therefore essential for board certification and ambulatory clinical excellence.

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Annual Influenza Immunization: Formulations, Enhanced Vaccines & Egg Allergy

Universal Recommendation & Seasonality

The ACIP recommends universal annual influenza vaccination for all individuals aged 6 months and older who do not have specific contraindications. Because influenza viruses undergo continuous antigenic variation through point mutations in surface glycoproteins (antigenic drift), annual reformulation of vaccines is required.

• Vaccination Timing: Vaccination should ideally be offered during September and October. Vaccination in July and August should generally be avoided for non-pregnant adults because antibody titers wane over the course of the 6- to 8-month season, potentially leaving patients vulnerable during late-winter peaks (February–March). Exceptions to avoid delayed administration include pregnant individuals in their third trimester (to protect the infant) and children requiring a 2-dose series.
• Unvaccinated Encounters: Vaccination should continue to be offered throughout the entire influenza season (even into February, March, or later) as long as influenza viruses are circulating.

Enhanced Formulations for Adults Aged ≥ 65 Years

Standard-dose unadjuvanted inactivated influenza vaccines elicit lower seroconversion rates and faster antibody waning in older adults. To overcome immunosenescence, ACIP preferentially recommends that adults aged 65 and older receive one of three enhanced influenza vaccines:

1. Quadrivalent High-Dose Inactivated Influenza Vaccine (HD-IIV4, Fluzone High-Dose Quadrivalent):
   • Antigen Content: Contains 60 μg of hemagglutinin (HA) per vaccine strain (total of 240 μg across 4 strains)—precisely 4 times the antigen content of standard-dose vaccines (15 μg HA per strain).
   • Clinical Evidence: Randomized double-blind trials demonstrate a 24% relative efficacy improvement in preventing laboratory-confirmed influenza compared to standard-dose vaccine, with substantial reductions in pneumonia hospitalizations and all-cause mortality.
2. Adjuvanted Inactivated Influenza Vaccine (aIIV4, Fluad Quadrivalent):
   • Mechanism: Contains standard-dose HA (15 μg per strain) formulated with MF59, an oil-in-water emulsion of squalene.
   • Immunologic Effect: MF59 recruits antigen-presenting cells (monocytes, macrophages, dendritic cells) to the local injection site, enhances antigen uptake, and stimulates broader, cross-reactive antibody responses against drifted viral strains.
3. Quadrivalent Recombinant Influenza Vaccine (RIV4, Flublok Quadrivalent):
   • Production Technology: Produced via recombinant DNA technology using a baculovirus expression vector system in a continuous insect cell line (Spodoptera frugiperda), completely free of chicken eggs, antibiotics, and live influenza virus.
   • Antigen Content: Contains 45 μg of hemagglutinin per strain (3 times the standard dose).
   • Clinical Evidence: Demonstrates superior relative efficacy compared to standard-dose inactivated vaccines in adults aged 50 and older.

[!IMPORTANT] Clinical Rule on Vaccine Availability: If none of the three preferentially recommended enhanced influenza vaccines (HD-IIV4, aIIV4, RIV4) is available at the clinical encounter, the patient should NOT be turned away or have vaccination delayed. An age-appropriate standard-dose unadjuvanted quadrivalent inactivated influenza vaccine should be administered immediately.

ACIP Guidance on Egg Allergy: The Complete Paradigm Shift

Historically, influenza vaccine guidance involved complex screening questionnaires dividing egg-allergic patients into those experiencing mild hives versus angioedema, respiratory distress, or anaphylaxis. Patients were subjected to 30-minute waiting periods, skin testing, or restricted exclusively to egg-free formulations (Flublok or Flucelvax).

The Current ACIP Guideline is Universal and Unconditional:

• Any licensed, recommended, age-appropriate influenza vaccine (egg-based or non-egg-based) may be administered to any person with an egg allergy of any severity.
• Egg allergy of any degree—including severe life-threatening anaphylaxis requiring epinephrine, emergency room resuscitation, or ICU admission—is no longer an ACIP contraindication or precaution to any influenza vaccine.
• No special post-vaccination observation periods (beyond the standard 15 minutes recommended for all vaccines to prevent syncope-related injury) or allergy subspecialty consultations are required.
• The only absolute contraindication is a documented history of severe allergic reaction (anaphylaxis) to a prior dose of influenza vaccine or a known severe allergy to a non-egg component of the vaccine.

Live Attenuated Influenza Vaccine (LAIV4, FluMist)

• Format & Target Population: Intranasal spray approved exclusively for healthy, non-pregnant individuals aged 2 through 49 years.
• Absolute Contraindications: Pregnancy, immunocompromising conditions (HIV with low CD4, chemotherapy, immunosuppressants), anatomical or functional asplenia, cerebrospinal fluid (CSF) leaks, cochlear implants, close contacts or caregivers of severely immunocompromised persons requiring protective isolation, and concurrent use of aspirin-containing therapy in children/adolescents.
• Antiviral Interaction: Antiviral medications (oseltamivir, zanamivir within 48 hours; peramivir within 5 days; baloxavir within 17 days) inhibit replication of the live attenuated vaccine virus, blunting efficacy. If taken, LAIV must be delayed or revaccination scheduled.

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COVID-19 Immunization: Formulations, Schedules & Immunocompromise

Vaccine Platforms and Formulations

COVID-19 vaccination continues to provide essential protection against hospitalization, intensive care admission, and post-acute sequelae of COVID-19 (PASC / Long COVID). Formulations are updated annually to target predominant circulating SARS-CoV-2 spike protein lineages (e.g., JN.1 and KP lineages):

1. mRNA Vaccines:
   • BNT162b2 (Pfizer-BioNTech / Comirnaty): Formulated in lipid nanoparticles encoding full-length prefusion-stabilized spike glycoprotein.
   • mRNA-1273 (Moderna / Spikevax): Lipid nanoparticle mRNA formulation.
2. Protein Subunit Vaccine:
   • NVX-CoV2373 (Novavax): Recombinant SARS-CoV-2 spike protein nanoparticles formulated with Matrix-M adjuvant (saponin-based). Useful alternative for patients with mRNA vaccine hesitancy or confirmed polyethylene glycol (PEG) allergy.

ACIP Routine Schedule for Immunocompetent Adults

• All adults aged 19 and older should receive 1 dose of the updated annual seasonal COVID-19 vaccine, regardless of their prior vaccination history, provided at least 8 weeks have elapsed since their most recent prior COVID-19 vaccine dose.

Regimen for Moderately or Severely Immunocompromised Adults

• Eligible Cohort: Solid organ transplant recipients, hematologic malignancy patients on active chemotherapy, CAR-T cell or hematopoietic stem cell transplant (HSCT) recipients within 2 years, advanced or untreated HIV (CD4 < 200 cells/μL), patients taking high-dose corticosteroids (≥ 20 mg prednisone equivalent daily for ≥ 14 days), and patients receiving B-cell depleting biologics (rituximab) or TNF inhibitors.
• Regimen: Recommended to receive an initial 3-dose series of updated mRNA vaccine, with the option to receive 1 or more additional updated doses at least 2 months following the last updated dose, guided by clinical judgment and shared decision-making to optimize circulating neutralizing antibody titers.

Rare Adverse Events: Myocarditis and Pericarditis

• Epidemiology: Rare cases of myocarditis and pericarditis have been observed following mRNA vaccination, predominantly in adolescent and young adult males (ages 12–29 years), typically within 7 days of the second dose.
• Clinical Course: The clinical presentation is overwhelmingly mild, with rapid resolution following short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) and rest.
• Risk-Benefit Calculus: The risk of severe myocardial injury, arrhythmias, multisystem inflammatory syndrome (MIS), and death from wild-type SARS-CoV-2 infection vastly exceeds the risk of post-vaccination myocarditis across all age demographics.

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Respiratory Syncytial Virus (RSV) Immunization in Older Adults & Pregnancy

Disease Burden and Pathophysiology

Respiratory syncytial virus is an enveloped, negative-sense single-stranded RNA pneumovirus that causes severe lower respiratory tract disease (LRTD) in older adults. In the United States, RSV is responsible for an estimated 60,000–160,000 hospitalizations and 6,000–10,000 deaths annually among adults aged 65 and older. The primary antigenic target for protective neutralizing antibodies is the RSV Fusion (F) glycoprotein, specifically stabilized in its prefusion conformation (preF).

Approved Adult Formulations

1. Arexvy (GSK): Recombinant RSV glycoprotein F stabilized in prefusion conformation (RSVPreF3, 120 μg) formulated with the AS01E adjuvant system (containing QS-21 saponin and monophosphoryl lipid A). FDA-approved for adults aged ≥ 60 years and, since June 2024, for adults aged 50–59 years at increased risk of RSV lower respiratory tract disease (LRTD).
2. Abrysvo (Pfizer): Bivalent recombinant RSV prefusion F protein containing 60 μg of subgroup A and 60 μg of subgroup B prefusion F antigens (unadjuvanted). FDA-approved for adults aged ≥ 60 years, for adults aged 18–59 years at increased risk of LRTD, AND for pregnant individuals at 32–36 weeks gestation.
3. mResvia (Moderna): mRNA vaccine (mRNA-1345) encoding the stabilized prefusion F glycoprotein encapsulated in lipid nanoparticles. FDA-approved for adults aged ≥ 60 years and for adults aged 18–59 years at increased risk of LRTD.

[!NOTE] Licensure is broader than the recommendation. Abrysvo and mResvia are licensed down to age 18 for at-risk adults, but as of the current schedule ACIP judged the evidence insufficient to recommend routine RSV vaccination in adults aged 18–49. Answer recommendation questions from the ACIP band (≥ 75 universal; 50–74 risk-based), not from the package insert.

ACIP Recommendations for Older Adults

• Adults Aged ≥ 75 Years: Universal recommendation for a single lifetime dose of any approved RSV vaccine (Arexvy, Abrysvo, or mResvia).
• Adults Aged 50–74 Years: Risk-stratified recommendation for a single lifetime dose if they have one or more high-risk conditions for severe RSV disease. ACIP voted in April 2025 to extend this band down from 60 to 50 years, and CDC adopted it in June 2025; the current CDC adult schedule reads "50 through 74 years." High-risk conditions include:
  • Chronic cardiovascular disease: Heart failure, coronary artery disease, cardiomyopathies
  • Chronic pulmonary disease: COPD, asthma, interstitial lung disease, cystic fibrosis
  • Chronic renal disease: End-stage renal disease (ESRD), hemodialysis, stage 4–5 CKD
  • Chronic liver disease: Cirrhosis, hepatic failure
  • Diabetes mellitus: Especially with end-organ damage or requiring pharmacotherapy
  • Severe obesity: Body mass index (BMI) ≥ 40 kg/m²
  • Immune compromise: Moderate or severe immunocompromising conditions
  • Congregate living: Residence in a nursing home or long-term care facility
• Dosing Frequency: RSV vaccination is currently administered as a single lifetime dose. It is not an annual seasonal booster. It may be coadministered with influenza and COVID-19 vaccines during the same encounter at distinct anatomical sites.
• Safety Profile: Post-licensure safety surveillance identified a rare association with Guillain-Barré syndrome (GBS), estimated at approximately 1 to 2 cases per 100,000 doses administered.

Maternal RSV Immunization (Protecting the Infant)

• Sole Approved Formulation: Abrysvo ONLY. (Arexvy is NOT approved in pregnancy due to a non-statistically significant imbalance in preterm births observed in clinical development).
• Gestational Window: Administered strictly between 32 0/7 and 36 6/7 weeks of gestation.
• Seasonality: Administered seasonally from September through January in most of the continental United States (timed to protect infants born during peak winter RSV transmission).
• Infant Protection Strategy: Maternal vaccination stimulates high titers of maternal neutralizing anti-F IgG, which actively cross the placenta via Fc receptors, conferring >80% protection against severe infant RSV lower respiratory tract disease during the first 6 months of life. If the mother receives Abrysvo at least 14 days prior to delivery, the infant does not need the long-acting monoclonal antibody nirsevimab (Beyfortus), unless born <34 weeks gestation or undergoing cardiopulmonary bypass.

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Streptococcus pneumoniae Immunization: The Modern Conjugate Era

Pathophysiology & Polysaccharide vs Conjugate Immunobiology

Streptococcus pneumoniae is an encapsulated gram-positive diplococcus with more than 100 known capsular serotypes. The polysaccharide capsule protects the bacterium from phagocytosis, facilitating colonization, mucosal invasion (otitis media, sinusitis, non-bacteremic community-acquired pneumonia), and Invasive Pneumococcal Disease (IPD)—defined as isolation of pneumococcus from normally sterile body sites (bacteremic pneumonia, meningitis, and septic shock), which carries a 10–20% mortality in older adults.

ACIP Pneumococcal Recommendations for Vaccine-Naive Adults

[!IMPORTANT] The age-based threshold moved from 65 to 50. On October 23, 2024 ACIP voted to recommend a single dose of PCV for all PCV-naive adults aged ≥ 50 years, down from the previous age ≥ 65 trigger (published as MMWR Morb Mortal Wkly Rep 2025;74:1–8). Questions written to the pre-2024 rule are now wrong; "defer the conjugate until age 65" is a classic stale distractor.

Adults eligible for pneumococcal immunization include:

1. All adults aged ≥ 50 years who have not previously received a pneumococcal conjugate vaccine (age-based recommendation, no risk condition required).
2. Adults aged 19–49 years with underlying medical conditions or risk factors:
   • Chronic medical conditions: Alcoholism, chronic heart disease (CHF, cardiomyopathies; excluding isolated hypertension), chronic liver disease (cirrhosis), chronic lung disease (COPD, asthma), cigarette smoking, diabetes mellitus.
   • High-risk conditions (immunocompromise, asplenia, leaks): Functional or anatomical asplenia (sickle cell disease, splenectomy), CSF leak, cochlear implant, chronic renal failure, nephrotic syndrome, congenital or acquired immunodeficiency, generalized malignancy, HIV infection, Hodgkin disease, immunosuppressive therapy (chemotherapy, systemic corticosteroids), solid organ transplant, multiple myeloma.

The Three Conjugate Options for Vaccine-Naive Adults

• Option 1: Single-Dose PCV20 (Prevnar 20) alone.
  • Administer 1 dose of PCV20. The pneumococcal series is complete. No subsequent PPSV23 is needed.
• Option 2: Single-Dose PCV21 (Capvaxive) alone (2024 ACIP Addition):
  • Contains capsular polysaccharides from 21 serotypes, 8 of which are unique to PCV21 (15A, 16F, 23A, 23B, 24F, 31, 35B, 39) and absent from PCV20 and PPSV23.
  • Specifically engineered to cover 84% of adult invasive pneumococcal disease serotypes (compared to ~52% covered by PCV20).
  • Administer 1 dose of PCV21. The series is complete. No subsequent PPSV23 is needed.
• Option 3: PCV15 (Vaxneuvance) Followed by PPSV23 (Pneumovax 23):
  • Administer 1 dose of PCV15, followed by a dose of PPSV23.
  • Standard Interval: Administer PPSV23 ≥ 1 year later for immunocompetent adults without high-risk conditions.
  • Shortened Interval: Administer PPSV23 ≥ 8 weeks later for adults with immunocompromising conditions, functional or anatomical asplenia, CSF leak, or cochlear implants.

Catch-Up Protocols for Adults Previously Vaccinated

• Previously Received PPSV23 Alone: Administer 1 dose of PCV20 or PCV21 at least 1 year after the last PPSV23 dose. The series is complete.
• Previously Received PCV13 Alone: Administer 1 dose of PCV20 or PCV21 at least 1 year after PCV13; OR complete the previously recommended series by administering PPSV23 (at least 1 year after PCV13 for immunocompetent, or at least 8 weeks for immunocompromised).
• Previously Received Both PCV13 and PPSV23: If all recommended prior doses were received, the patient is considered protected. However, clinicians may administer 1 dose of PCV20 or PCV21 at least 5 years after the last pneumococcal dose based on shared clinical decision-making, particularly in adults with high-risk conditions.

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Adult Respiratory Vaccine Master Summary Table