2.1 Respiratory Viral Pathogens: Influenza, COVID-19, and RSV

2.1 Respiratory Viral Pathogens: Influenza, COVID-19, and RSV

Respiratory viral infections represent the leading cause of vaccine-preventable outpatient visits, hospitalizations, and seasonal excess mortality across all age demographics. Certified Pharmacy Technicians (CPhTs) administering or preparing immunizations must possess an in-depth understanding of the pathophysiology, antigenic evolution, high-risk clinical complications, and specific vaccine product formulations associated with Influenza, SARS-CoV-2 (COVID-19), and Respiratory Syncytial Virus (RSV).

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1. Influenza Viruses (Orthomyxoviridae)

Influenza is an acute, febrile respiratory illness caused by enveloped, single-stranded, negative-sense RNA viruses belonging to the family Orthomyxoviridae. Influenza viruses are classified into types A, B, C, and D, with types A and B responsible for recurring seasonal human epidemics.

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|                        INFLUENZA VIRION ARCHITECTURE                        |
|                                                                             |
|                      [ Hemagglutinin (HA) Spikes ]                          |
|                     - Mediates viral attachment to                          |
|                       host sialic acid receptors                            |
|                     - Major target for neutralizing antibodies              |
|                                    │                                        |
|                                ┌───┴───┐                                    |
|                           ┌────┘       └────┐                               |
|                          ╱   (Lipid Bilayer) ╲                              |
|                         │   ┌───────────────┐ │                             |
|     [ Neuraminidase ]───┤   │ Segmented RNA │ ├───[ M2 Ion Channel ]        |
|     - Cleaves sialic    │   │  (8 segments) │ │   - Target of amantadine    |
|       acid to release   │   └───────────────┘ │     (Type A only)           |
|       progeny virions    ╲                   ╱                              |
|                           └────┐       ┌────┘                               |
|                                └───┬───┘                                    |
|                                    │                                        |
|                        [ M1 Matrix Protein ]                                |
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Viral Surface Glycoproteins

• Hemagglutinin (HA): A trimeric glycoprotein that binds terminal sialic acid residues on host respiratory epithelial cell surfaces, facilitating receptor-mediated endocytosis and viral membrane fusion. HA is the primary antigen against which host neutralizing antibodies are directed.
• Neuraminidase (NA): A tetrameric glycoprotein enzyme that hydrolyzes the glycosidic linkage between sialic acid and adjacent sugar residues. This enzymatic cleavage frees budding progeny virions from the host cell surface and prevents viral aggregation, allowing infection to spread down the tracheobronchial tree.

Antigenic Variation: Drift vs. Shift

The structural mutability of influenza surface antigens drives the requirement for continuous epidemiologic surveillance and annual vaccine updates.

Pathophysiology and Clinical Complications

Transmission occurs via respiratory droplets, small-particle aerosols, and indirect contact with contaminated fomites. Following an incubation period of 1 to 4 days (average 2 days), viral replication destroys ciliated respiratory epithelium, stripping the mucociliary escalator and triggering an intense pro-inflammatory cytokine cascade (interferon-alpha, IL-6, TNF-alpha).

Classic Clinical Presentation:

• Abrupt onset of high fever (100°F–104°F / 37.8°C–40.0°C), rigors, diaphoresis
• Severe myalgias (prominently in the back and legs) and profound fatigue
• Nonproductive cough, sore throat, substernal burning, and severe headache

High-Risk Complications:

1. Secondary Bacterial Pneumonia: Most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), and Haemophilus influenzae. Classically presents as a biphasic illness where the patient temporarily improves from the viral prodrome, then abruptly deteriorates with recrudescent fever, purulent sputum, and lobar consolidation.
2. Primary Viral Pneumonia: Rapidly progressive bilateral infiltrates, diffuse alveolar damage, and acute respiratory distress syndrome (ARDS) with high mortality.
3. Cardiovascular Events: Significant increase in acute myocardial infarction and ischemic stroke within 7 to 14 days following acute influenza infection.
4. Reye Syndrome: Severe hepatic steatosis and non-inflammatory encephalopathy associated with the administration of aspirin or salicylate-containing products to children and adolescents during acute influenza or varicella infections.

Influenza Vaccine Product Formulations

Current U.S. formulation rule: Beginning with the 2024–2025 season, all U.S. influenza vaccines returned to trivalent composition. Product names and abbreviations in this guide therefore use IIV3, ccIIV3, RIV3, aIIV3, HD-IIV3, and LAIV3; verify the current season label before preparation.

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|                             INFLUENZA VACCINE CLASSIFICATIONS & DOSING                            |
|                                                                                                   |
|   1. STANDARD-DOSE INACTIVATED (IIV)                                                              |
|      - Grown in embryonated chicken eggs; inactivated with formaldehyde or beta-propiolactone.    |
|      - Standard dose: 15 mcg HA per strain (e.g., Afluria, Fluarix, Flulaval, Fluzone).           |
|      - Approved for ages ≥ 6 months. Standard IM injection.                                       |
|                                                                                                   |
|   2. CELL CULTURE-BASED INACTIVATED (ccIIV)                                                       |
|      - Propagated in Madin-Darby Canine Kidney (MDCK) cells; avoids egg-adaptive mutations.       |
|      - Product: Flucelvax. Approved for ages ≥ 6 months. (Contains no egg protein).              |
|                                                                                                   |
|   3. RECOMBINANT INFLUENZA VACCINE (RIV)                                                          |
|      - Produced via baculovirus expression system in insect cells (Spodoptera frugiperda).        |
|      - Product: Flublok. 100% egg-free. Contains 3x standard antigen (45 mcg HA per strain).     |
|      - Approved for ages ≥ 18 years.                                                              |
|                                                                                                   |
|   4. ADJUVANTED INACTIVATED (aIIV)                                                                |
|      - Standard antigen dose (15 mcg HA per strain) formulated with MF59 (squalene oil emulsion).  |
|      - Product: Fluad. Enhances antigen presentation and antibody titers in immunosenescent hosts.|
|      - Approved for ages ≥ 65 years.                                                              |
|                                                                                                   |
|   5. HIGH-DOSE INACTIVATED (HD-IIV)                                                               |
|      - Contains 4x standard antigen dose (60 mcg HA per strain) to overcome immunosenescence.     |
|      - Product: Fluzone High-Dose. Approved for ages ≥ 65 years.                                  |
|                                                                                                   |
|   6. LIVE ATTENUATED INFLUENZA VACCINE (LAIV)                                                     |
|      - Cold-adapted, temperature-sensitive reassortants that replicate only in the cool nasopharynx.|
|      - Product: FluMist. Intranasal spray (0.2 mL total; 0.1 mL per nostril).                     |
|      - Approved ONLY for healthy non-pregnant individuals aged 2 through 49 years.                |
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[!IMPORTANT] Preferential Recommendations for Adults Aged 65 Years and Older: Due to age-related immunosenescence (diminished humoral and cell-mediated immune responses), the CDC's Advisory Committee on Immunization Practices (ACIP) preferentially recommends one of three enhanced formulations for all individuals aged 65 and older:

1. Fluzone High-Dose (HD-IIV)
2. Flublok recombinant (RIV)
3. Fluad adjuvanted (aIIV)

If none of these three preferentially recommended vaccines is available at the time of administration, an age-appropriate standard-dose unadjuvanted influenza vaccine should be administered without delaying immunization.

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2. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 / COVID-19)

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus belonging to the genus Betacoronavirus within the family Coronaviridae. It is the causative pathogen of Coronavirus Disease 2019 (COVID-19).

Viral Pathophysiology and Cell Entry

1. Receptor Binding: The surface Spike (S) glycoprotein contains a Receptor-Binding Domain (RBD) within its S1 subunit that binds with high affinity to human Angiotensin-Converting Enzyme 2 (ACE2) receptors. ACE2 is abundantly expressed on type II pneumocytes, ciliated nasal epithelial cells, vascular endothelial cells, myocardial tissue, and renal tubular cells.
2. Host Protease Cleavage: Host cell surface transmembrane protease serine 2 (TMPRSS2) or endosomal cathepsin L cleaves the spike protein at the S1/S2 and S2' sites, triggering conformational changes in the S2 subunit that mediate fusion of the viral envelope with the host membrane.
3. Systemic Pathophysiology: Following viral replication, downregulation of ACE2 leads to local accumulation of angiotensin II, promoting vasoconstriction, vascular permeability, and inflammation. Severe disease is characterized by a dysregulated systemic inflammatory response ("cytokine storm" marked by elevated IL-1, IL-6, CRP, and ferritin), microvascular endothelial injury, platelet activation, diffuse microthrombi formation, and ARDS.

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|                        SARS-CoV-2 CELL ENTRY MECHANISM                      |
|                                                                             |
|          [ SARS-CoV-2 Virion ]                                              |
|                    │ (Spike Glycoprotein)                                   |
|                    ▼                                                        |
|         ┌──────────────────────┐                                            |
|         │ Spike RBD binds ACE2 │ ◄─── Expressed on Type II Pneumocytes      |
|         └──────────┬───────────┘      and Vascular Endothelium              |
|                    │                                                        |
|                    ▼                                                        |
|         ┌──────────────────────┐                                            |
|         │  TMPRSS2 Cleavage    │ ◄─── Priming at S1/S2 junction             |
|         └──────────┬───────────┘                                            |
|                    │                                                        |
|                    ▼                                                        |
|         ┌──────────────────────┐                                            |
|         │ Viral Membrane Fusion│ ───► Delivery of (+)ssRNA into cytoplasm    |
|         └──────────────────────┘                                            |
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COVID-19 Vaccine Platforms

Clinical Guidance and Co-administration

• Current Recommendation: For the 2025–2026 season, CDC recommends COVID-19 vaccination for people aged 6 months and older using individual-based decision-making. Benefit is greatest for people at increased risk of severe disease; the product and number of doses depend on age, immune status, and vaccination history.
• Co-administration: COVID-19 vaccines may be administered simultaneously with seasonal influenza and RSV vaccines during the same visit. Injections should be administered in anatomically distinct sites (e.g., different arms, or separated by at least 1 inch if given in the same deltoid muscle).

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3. Respiratory Syncytial Virus (RSV)

Respiratory Syncytial Virus is an enveloped, negative-sense, single-stranded RNA virus belonging to the family Pneumoviridae (genus Orthopneumovirus). It possesses two major antigenic subtypes: RSV-A and RSV-B.

Pathophysiology and Structural Biology

The viral envelope contains two major glycoproteins essential for pathogenesis:

• G Protein (Attachment Glycoprotein): Mediates initial tethering to host ciliated airway epithelial cells.
• F Protein (Fusion Glycoprotein): Mediates viral envelope fusion with the host cell membrane and drives cell-to-cell fusion, forming characteristic multinucleated giant cells (syncytia).

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|                        RSV FUSION (F) PROTEIN DYNAMICS                      |
|                                                                             |
|   [ PREFUSION F CONFORMATION (pre-F) ] ──► Highly unstable, metastable      |
|   - Contains primary neutralizing epitopes  conformation on virion surface  |
|     (Site Ø and Site V)                     (Target of modern vaccines)     |
|                    │                                                        |
|                    ▼ (Triggered during cell entry)                          |
|   [ POSTFUSION F CONFORMATION (post-F)] ─► Highly stable, elongated         |
|   - Lacks Site Ø neutralizing epitopes;     conformation following membrane |
|     poor immunogen for neutralizing         fusion                          |
|     antibody induction                                                      |
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Clinical Spectrum

• Infants (< 12 months): Leading cause of infant hospitalization in the United States. Viral necrosis of bronchiolar epithelium and peribronchiolar lymphocytic infiltration lead to mucus plugging, air trapping, atelectasis, wheezing, tachypnea, and severe bronchiolitis.
• Older Adults and High-Risk Adults: Causes severe lower respiratory tract disease (LRTD), viral pneumonia, and life-threatening exacerbations of underlying chronic obstructive pulmonary disease (COPD), asthma, and congestive heart failure (CHF).

Modern RSV Vaccine and Prophylaxis Lineup

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|                                 RSV PREVENTIVE PRODUCTS MATRIX                                    |
|                                                                                                   |
|   1. AREXVY (GSK)                                                                                 |
|      - Type: Recombinant stabilized prefusion F protein (RSVPreF3).                               |
|      - Adjuvant: Formulated with AS01E adjuvant system (contains QS-21 and MPL).                  |
|      - Adult use: Follow the current FDA age indication and CDC recommendation; CDC recommends a single RSV vaccine dose for all adults aged ≥75 years and adults aged 50–74 years at increased risk.                  |
|      - Maternal use: Arexvy is not approved for maternal immunization; only Abrysvo is used in the current pregnancy recommendation.                |
|                                                                                                   |
|   2. ABRYSVO (Pfizer)                                                                             |
|      - Type: Bivalent recombinant prefusion F protein (subgroups A and B).                        |
|      - Adjuvant: UNADJUVANTED.                                                                    |
|      - Indications:                                                                               |
|        (a) Adults within the current product label; CDC recommends a single dose at age ≥75 or age 50–74 with increased risk.                          |
|        (b) MATERNAL IMMUNIZATION: Pregnant individuals at 32 0/7 through 36 6/7 weeks of          |
|            gestation to protect infants from birth through 6 months of age.                       |
|                                                                                                   |
|   3. mRESVIA (Moderna)                                                                            |
|      - Type: mRNA platform (mRNA-1345) encoding stabilized prefusion F glycoprotein in LNPs.      |
|      - Adult use: Follow the current product label and CDC recommendation (all adults ≥75 and adults 50–74 at increased risk).                                                        |
|                                                                                                   |
|   4. NIRSEVIMAB (Beyfortus - Sanofi/AstraZeneca)                                                  |
|      - Type: Recombinant human IgG1κ long-acting monoclonal antibody targeting Site Ø of pre-F.   |
|      - Mechanism: Passive immunity (provides immediate neutralizing antibody protection).         |
|      - Indication: All infants < 8 months born during or entering their first RSV season whose     |
|        mothers did NOT receive maternal RSV vaccine ≥ 14 days before delivery; and high-risk      |
|        children aged 8–19 months entering their second RSV season.                                |
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[!NOTE] Maternal Vaccination vs. Infant Monoclonal Antibody (ACIP Rule of One): To prevent infant RSV lower respiratory tract disease, ACIP recommends either maternal vaccination with Abrysvo at 32 through 36 gestational weeks OR infant passive immunization with nirsevimab (Beyfortus) or clesrovimab (Enflonsia), as age- and season-appropriate. In the vast majority of cases, infants do not need both. If the mother received Abrysvo at least 14 days prior to delivery, the infant is considered protected via transplacental IgG transfer.

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4. Clinical Comparison Table: Major Respiratory Viral Pathogens