1.3 Vaccine Types, Platforms, and Adjuvants
Key Takeaways
- Live attenuated vaccines contain weakened replicating organisms that elicit robust, long-lasting humoral and cell-mediated immunity. Most—including MMR, varicella, LAIV, and oral Ty21a—are contraindicated during pregnancy; yellow fever is a precaution requiring individual risk-benefit assessment. Severe immunocompromise generally contraindicates live vaccines.
- Inactivated, subunit, and toxoid vaccines (e.g., IPV, Hepatitis A, Recombinant Zoster, DTaP/Tdap) contain non-replicating antigens that cannot cause the target infectious disease, making them safe for immunocompromised patients, though they generally require multi-dose series and boosters.
- Pure polysaccharide vaccines (PPSV23) stimulate B-cells independently of T-cells (T-independent), failing to elicit immune memory or adequate responses in children under 2 years of age; conjugate vaccines (PCV15, PCV20, Hib) link polysaccharides to protein carriers, inducing T-dependent immune memory and strong infantile protection.
- Modern mRNA vaccines (Pfizer-BioNTech, Moderna) deliver lipid nanoparticle-encapsulated synthetic mRNA encoding viral target antigens (e.g., SARS-CoV-2 spike protein) for direct cellular translation without entering the cell nucleus or integrating into host genomic DNA.
- Adjuvants (such as aluminum salts, AS01B in Shingrix, MF59 in Fluad, and CpG 1018 in Heplisav-B) are immunostimulatory additives that enhance antigen presentation, recruit innate immune cells, and enable dose sparing without containing live infectious agents.
Vaccine Types, Platforms, and Adjuvants
Core Principle: Vaccines fall into distinct pharmacological and biological categories based on how the antigen is manufactured, formulated, and delivered. The vaccine platform dictates its immunogenic potency, route of administration, storage requirements (cold chain), multi-dose booster schedule, and clinical safety profile in vulnerable populations.
Pharmacy technicians must master the fundamental differences between vaccine platforms to prevent administration errors, ensure proper cold chain storage, understand clinical contraindications, and assist pharmacists with patient screening.
1. Live Attenuated Vaccines (LAVs)
Live attenuated vaccines are created by modifying wild disease-causing viruses or bacteria in a laboratory (typically through repeated passage in cell cultures or tissue media). The resulting organism is attenuated (weakened): it retains the ability to replicate and express native antigens inside the human host, but it generally cannot cause clinical disease in an immunocompetent person.
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| LIVE ATTENUATED VACCINE PLATFORM |
| |
| [WILD VIRUS/BACTERIA] ---> [SERIAL PASSAGE / ATTENUATION] |
| | |
| v |
| [ATTENUATED VACCINE STRAIN] |
| | |
| v (Administered to Host) |
| [CONTROLLED REPLICATION] |
| - Mimics natural subclinical infection |
| - Replicates intracellularly & presented on MHC Class I & II |
| - Stimulates potent CD8+ Cytotoxic T-Cells + CD4+ T-Cells + Plasma B-Cells|
| - Induces secretory IgA (mucosal) and systemic IgG |
| - Yields durable, long-term immunity in 1–2 doses |
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Clinical Characteristics of Live Vaccines
- Immunological Potency: LAVs generate the strongest, most durable immune response because the replicating organism presents multiple native epitopes over several days, stimulating robust humoral (IgG and mucosal IgA) and potent cellular (CD8+ cytotoxic T-cell) memory.
- Dosing: Typically effective with only 1 or 2 doses (e.g., MMR series confers ~97% lifetime protection).
- Storage Sensitivity: Live viral vaccines are fragile. Several require frozen storage (e.g., Varicella and MMRV must be stored between -50°C and -15°C / -58°F and +5°F) and protect-from-light packaging.
Major Live Attenuated Vaccines
- MMR: Priorix is administered SC; M-M-R II may be administered SC or IM. Always verify the specific product label.
- Varicella (Varivax): Varicella-zoster live virus (SC, stored frozen).
- MMRV (ProQuad): Measles, Mumps, Rubella, Varicella combination (SC, stored frozen).
- Rotavirus (Rotarix [RV1], RotaTeq [RV5]): Live attenuated rotaviruses (Oral [PO] only; never inject).
- LAIV3 (FluMist): Live Attenuated Influenza Vaccine (Intranasal [NAS] spray only; approved for healthy, non-pregnant individuals aged 2 through 49 years).
- Yellow Fever (YF-Vax): Live 17D strain (SC).
- Oral Typhoid (Ty21a / Vivotif): Live attenuated Salmonella enterica serovar Typhi (Oral capsules; refrigerated; taken every other day for 4 doses).
Contraindications and Precautions for Live Vaccines
Because live attenuated organisms replicate in the host, they carry a risk of uncontrolled replication and disseminated disease in individuals with compromised immune function:
- Pregnancy: MMR, varicella, MMRV, LAIV, and oral Ty21a are contraindicated during pregnancy because of theoretical fetal risk. Yellow fever is an important exception: pregnancy is a precaution, and vaccination may proceed when unavoidable exposure risk outweighs vaccine risk. Follow vaccine-specific guidance; for live viral vaccines, conception is generally deferred for 4 weeks after vaccination.
- Severe Immunocompromise: Includes patients with:
- Congenital immunodeficiencies.
- Advanced HIV infection with severe immunosuppression (CD4+ T-lymphocyte count < 200 cells/mm³ or < 15% in children).
- Hematologic malignancies (leukemia, lymphoma, multiple myeloma).
- Solid organ or bone marrow transplant recipients on immunosuppressive pharmacotherapy.
- Active chemotherapy or biological immunosuppressants (TNF-alpha inhibitors, anti-CD20 monoclonal antibodies like rituximab).
- High-dose systemic corticosteroid therapy defined as ≥ 20 mg/day of prednisone (or ≥ 2 mg/kg/day) for 14 or more consecutive days.
[!IMPORTANT] The 4-Week Live Vaccine Spacing Rule (ACIP): If two live injectable or live intranasal vaccines (e.g., MMR and Varicella, or MMR and FluMist) are not administered on the same calendar day, they must be separated by a minimum interval of 4 weeks (28 days). If administered closer than 28 days apart, the second vaccine dose is considered invalid (blunted by interferon release from the first dose) and must be repeated 4 weeks after the invalid dose.
2. Inactivated Whole-Organism Vaccines
Inactivated vaccines are produced by growing the target pathogenic virus or bacterium in culture and subsequently killing (inactivating) it using heat, radiation, or chemicals (such as formalin or beta-propiolactone).
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| INACTIVATED WHOLE-ORGANISM VACCINE |
| |
| [WILD VIRUS/BACTERIA] ---> [CHEMICAL INACTIVATION (FORMALIN)] |
| | |
| v |
| [KILLED, NON-REPLICATING ANTIGEN] |
| | |
| v (Administered to Host) |
| - Cannot replicate, mutate, or cause disease |
| - Purely humoral (B-cell / antibody) response; minimal CD8+ T-cell response|
| - Completely safe in immunocompromised & pregnant patients |
| - Requires multiple doses + periodic boosters to sustain protective titers|
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Clinical Characteristics
- Safety: Because the pathogen is completely dead, it cannot replicate, cannot revert to virulence, and cannot cause infectious disease, even in severely immunocompromised or pregnant patients.
- Immune Kinetics: Does not infect host cells; processed predominantly via MHC Class II pathways, generating primarily a humoral antibody response with minimal cytotoxic T-cell activation. Antibody titers decline over time, requiring an initial multi-dose primary series followed by periodic booster doses.
Major Inactivated Whole Vaccines
- Inactivated Polio Vaccine (IPV / IPOL / Salk Vaccine): Contains inactivated poliovirus types 1, 2, and 3 (Intramuscular [IM] or Subcutaneous [SC]). Note: Oral Polio Vaccine (OPV / Sabin) was a live attenuated vaccine discontinued in the U.S. in 2000 to eliminate vaccine-associated paralytic poliomyelitis (VAPP).
- Hepatitis A (Havrix, Vaqta): Inactivated hepatitis A whole viral particles (IM; 2-dose series separated by 6–18 months).
- Rabies Vaccine (Imovax, RabAvert): Inactivated rabies virus (IM; used for pre-exposure prophylaxis and post-exposure prophylaxis with RIG).
3. Subunit, Recombinant, Toxoid, and Conjugate Platforms
Rather than introducing a whole microbe, modern biotechnology isolates or synthesizes the specific antigenic components necessary to elicit a targeted, protective immune response.
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| SUBUNIT, RECOMBINANT & TOXOID PLATFORMS |
| |
| [RECOMBINANT PROTEIN] [VIRUS-LIKE PARTICLE] [TOXOID] |
| e.g., HBsAg in Yeast e.g., HPV L1 Capsid e.g., Tetanus/ |
| (Engerix-B, Recombivax) (Gardasil 9) Diphtheria Toxoid |
| | | | |
| +-------------------------+-------------------------+ |
| | |
| v |
| Targeted Epitope Presentation to B-Cells |
| + Adjuvant-Enhanced Immune Stimulation |
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1. Subunit and Recombinant Antigen Vaccines
- Hepatitis B Vaccines (Engerix-B, Recombivax HB): Manufactured by inserting the genetic plasmid coding for Hepatitis B surface antigen (HBsAg) into Saccharomyces cerevisiae (baker's yeast). The yeast expresses HBsAg, which is harvested and purified.
- Recombinant Zoster Vaccine (RZV / Shingrix): Contains recombinant glycoprotein E (gE) of the Varicella-Zoster Virus combined with the AS01B adjuvant system. Administered as a 2-dose IM series (separated by 2 to 6 months) for adults aged 50+ and immunocompromised adults aged 19+. Shingrix replaced the historical live zoster vaccine (Zostavax) due to superior efficacy (>90% protection) and safety in immunocompromised patients.
- Human Papillomavirus (9vHPV / Gardasil 9): Composed of recombinant Virus-Like Particles (VLPs) of the major capsid protein (L1) covering 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, 58). VLPs mimic viral structure to trigger high neutralizing antibody titers but contain zero viral DNA.
- Recombinant Influenza (RIV3 / Flublok): Completely egg-free vaccine produced by expressing recombinant hemagglutinin (HA) in an insect cell baculovirus system.
2. Toxoid Vaccines
Certain bacteria cause disease not through invasive tissue destruction, but by secreting soluble exotoxins. Toxoid vaccines contain bacterial exotoxins that have been chemically modified (inactivated with formaldehyde) to neutralize their toxicity while preserving their antigenic structure.
- Mechanism: Induce neutralizing antitoxin antibodies (IgG) that bind and neutralize wild bacterial toxins.
- Examples:
- Diphtheria Toxoid (Corynebacterium diphtheriae)
- Tetanus Toxoid (Clostridium tetani)
- Formulated in combination vaccines: DTaP (pediatric, < 7 years), Tdap (adolescent/adult booster with reduced diphtheria and pertussis components denoted by lowercase letters), DT, and Td.
4. Pure Polysaccharide vs. Polysaccharide-Conjugate Vaccines
One of the most critical immunological concepts tested on the PTCB exam is the distinction between pure polysaccharide vaccines and protein-conjugated polysaccharide vaccines.
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| PURE POLYSACCHARIDE vs. CONJUGATE IMMUNOLOGICAL PATHWAYS |
| |
| [PURE POLYSACCHARIDE (PPSV23)] |
| - Pure bacterial capsule sugars |
| - B-Cell Receptor Crosslinking ONLY (T-CELL INDEPENDENT) |
| - Result: IgM > IgG, NO Memory B-Cells, INEFFECTIVE IN CHILDREN < 2 YEARS |
| |
| [CONJUGATE VACCINE (PCV15, PCV20, PCV21, Hib, MenACWY)] |
| - Polysaccharide chemically linked to Carrier Protein (e.g., CRM197) |
| - B-Cell internalizes conjugate & presents peptides on MHC II |
| - Helper CD4+ T-Cell recruited (T-CELL DEPENDENT) |
| - Result: High-affinity IgG, DURABLE MEMORY CELLS, EFFECTIVE IN INFANTS |
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The T-Independent vs. T-Dependent Mechanism
| Immunological Feature | Pure Polysaccharide Vaccines | Polysaccharide-Conjugate Vaccines |
|---|---|---|
| Composition | Pure capsular polysaccharide chains without protein. | Capsular polysaccharide covalently linked to an immunogenic protein carrier (e.g., $CRM_{197}$ diphtheria mutant toxin, tetanus toxoid). |
| T-Cell Involvement | T-Cell Independent (TI-2): Directly cross-links B-cell receptors. No T-cell help. | T-Cell Dependent (TD): Carrier protein peptide presented via MHC Class II to CD4+ Helper T-cells. |
| Efficacy in Children < 2 Years | POOR / INEFFECTIVE: Children under 24 months have immature splenic marginal zones and cannot respond to TI-2 antigens. | HIGHLY EFFECTIVE: Induces strong, protective immune responses in infants as young as 6 to 8 weeks of age. |
| Immunological Memory | NO: Does not generate memory B-cells. Repeated doses do not elicit anamnestic booster responses (may cause hyporesponsiveness). | YES: Generates long-lived memory B-cells and memory T-cells. Subsequent doses produce massive booster responses. |
| Antibody Profile | Modest IgM, low-affinity IgG, rapid titer decline. | High-affinity, class-switched IgG with long-term persistence. |
| Representative Vaccines | • PPSV23 (Pneumovax 23 - 23-valent pneumococcal polysaccharide) | • PCV15 (Vaxneuvance), PCV20 (Prevnar 20), PCV21 (Capvaxive)<br>• Hib (ActHIB, PedvaxHIB, Hiberix)<br>• MenACWY (Menveo, MenQuadfi) |
5. Genetic & Viral Vector Platforms: mRNA and Adenovirus Delivery
Recent biotechnology innovations have introduced genetic platforms that instruct host cells to transiently manufacture the target antigen in situ.
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| mRNA VACCINE MECHANISM (LNP DELIVERY) |
| |
| [SYNTHETIC mRNA] + [LIPID NANOPARTICLE (LNP)] |
| | |
| v (Endocytosis into Host Muscle Cell) |
| [CYTOPLASMIC RELEASE OF mRNA] |
| | |
| +---> (Translated by Host Ribosomes) ---> [SPIKE PROTEIN SYNTHESIS]|
| | | |
| x (DOES NOT ENTER NUCLEUS; NO DNA ALTERATION) v |
| | [MHC I & MHC II DISPLAY] |
| v (Degraded rapidly within days) | |
| [CELLULAR & HUMORAL ADAPTIVE IMMUNE ACTIVATION] <---------+ |
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1. Messenger RNA (mRNA) Vaccines (Pfizer-BioNTech Comirnaty, Moderna Spikevax)
- Structure: Encapsulates synthetic nucleoside-modified messenger RNA encoding the viral target antigen (e.g., SARS-CoV-2 Spike glycoprotein) inside a Lipid Nanoparticle (LNP) vehicle.
- Function of the Lipid Nanoparticle (LNP):
- Protects fragile mRNA molecules from rapid enzymatic degradation by extracellular ribonucleases (RNases).
- Facilitates endocytosis across the host cell phospholipid membrane into the cytoplasm.
- Intracellular Processing: Once inside the cytoplasm, host cell ribosomes translate the mRNA into target viral protein. The synthesized antigen is expressed on the cell membrane and processed through both MHC Class I (activating CD8+ cytotoxic T-cells) and MHC Class II pathways (activating CD4+ helper T-cells and plasma B-cells).
- Essential Clinical & Exam Facts:
- mRNA never enters the host cell nucleus and cannot alter, integrate into, or interact with host genomic DNA.
- mRNA does not contain replicating enzymes; it is naturally degraded by cellular ribonucleases within days.
- Ultra-cold storage requirements: Undiluted Pfizer-BioNTech multi-dose vials historically required ultra-low temperature freezers (-90°C to -60°C / -130°F to -76°F), reflecting mRNA thermodynamic fragility.
2. Viral Vector Vaccines (Janssen/J&J Ad26.COV2.S, AstraZeneca ChAdOx1)
- Uses a modified, replication-incompetent virus (such as human Adenovirus 26 or chimpanzee adenovirus) as a delivery vector carrying the gene coding for the target antigen. The vector enters host cells and delivers the genetic code into the nucleus for transcription into mRNA and subsequent translation into antigen.
6. Adjuvants: Chemistry, Mechanisms, and Clinical Applications
An adjuvant (from the Latin adjuvare, meaning "to help") is an ingredient added to a non-live vaccine formulation that enhances, broadens, and accelerates the immune response to the co-administered antigen.
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| FOUR ROLES OF VACCINE ADJUVANTS |
| |
| 1. [DOSE SPARING] --> Lowers required antigen dose per injection |
| 2. [DEPOT FORMATION] --> Prolongs antigen exposure at injection site |
| 3. [INNATE RECRUITMENT] --> Activates TLRs, dendritic cells & cytokines |
| 4. [OVERCOMING SENESCENCE]--> Boosts protective titers in older adults |
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Key Adjuvants in Modern Clinical Practice
| Adjuvant System | Chemical Composition | Key Vaccines | Mechanism of Action & Clinical Pearl |
|---|---|---|---|
| Aluminum Salts (Alum) | Aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate | DTaP, Tdap, Hepatitis A, Hepatitis B (Engerix-B), PCV15/20, Hib, HPV9 | Depot effect & Th2 stimulation. Forms a physical precipitate at the injection site that slowly releases antigen, stimulates NLRP3 inflammasome, and promotes high antibody titers. Used safely for >80 years. |
| AS01B | Liposome-based system containing QS-21 (saponin tree bark extract) + MPL (monophosphoryl lipid A) | Shingrix (RZV), Arexvy (RSV) | Potent Th1 cellular & antibody activator. MPL binds TLR4 while QS-21 activates caspase-1. Elicits extraordinary CD4+ T-cell and neutralizing antibody titers in older adults, overcoming immunosenescence. Causes high local reactogenicity (soreness, fatigue). |
| MF59 | Squalene-based oil-in-water emulsion | Fluad (adjuvanted influenza for adults ≥65) | Cellular recruitment. Squalene emulsion recruits antigen-presenting cells to the injection site, promotes antigen drainage into lymph nodes, and broadens cross-reactive antibody coverage in elderly patients. |
| CpG 1018 | Synthetic 22-mer unmethylated cytosine-phosphoguanine oligonucleotide | Heplisav-B (HepB-CpG for adults ≥18) | Toll-Like Receptor 9 (TLR9) Agonist. Mimics bacterial DNA to activate dendritic cells and B-cells. Enables a 2-dose series (given at 0 and 1 month) that achieves >95% seroprotection, compared to a 3-dose, 6-month series with traditional alum-adjuvanted HepB. |
| Matrix-M | Saponin-based nanoparticle adjuvant | Novavax COVID-19 (NVX-CoV2373) | Saponin nanoparticles enhance recruitment of antigen-presenting cells and stimulate balanced Th1/Th2 responses to recombinant spike protein nanoparticles. |
7. Master Summary Table: Vaccine Platforms, Storage, and Routes
The following comprehensive reference table synthesizes vaccine classifications, representative products, standard administration routes, storage parameters, and core clinical pearls tested on the PTCB exam:
| Platform Category | Representative Vaccines | Standard Route | Storage Temperature Range | Key Clinical Pearls & Safety Rules | | :--- | :--- | :--- | :--- | | Live Attenuated Viral | MMR (M-M-R II / Priorix) | Product-specific: M-M-R II SC or IM; Priorix SC | Product-specific: Priorix refrigerated; M-M-R II refrigerated or frozen | Reconstitute only with the supplied diluent, protect from light, and follow the package insert for route, storage, and beyond-use time. Contraindicated in pregnancy and severe immunocompromise. | | Live Attenuated Viral | Varicella (Varivax), MMRV (ProQuad) | SC | FREEZER ONLY (-50°C to -15°C / -58°F to +5°F) | Must remain frozen until reconstitution. Administer within 30 minutes of reconstitution or discard. | | Live Attenuated Viral | Rotavirus (Rotarix, RotaTeq) | ORAL (PO) | Refrigerator (2°C to 8°C) | Oral administration ONLY. Never inject. Do not repeat dose if infant spits out or regurgitates. | | Live Attenuated Viral | LAIV3 (FluMist) | INTRANASAL (NAS) | Refrigerator (2°C to 8°C) | 0.2 mL total dose (0.1 mL per nostril). Approved only for healthy non-pregnant ages 2–49. | | Inactivated Whole Virus | Hepatitis A (Havrix, Vaqta) | IM | Refrigerator (2°C to 8°C) | 2-dose series separated by 6–18 months. Highly immunogenic. Do NOT freeze. | | Inactivated Whole Virus | Inactivated Polio (IPOL / IPV) | IM or SC | Refrigerator (2°C to 8°C) | Salk vaccine. Completely non-replicating; cannot cause vaccine-associated paralytic polio. | | Recombinant Subunit + Adjuvant | Recombinant Zoster (Shingrix / RZV) | IM | Refrigerator (2°C to 8°C) | 2-dose series (0, 2–6 months). Reconstitute lyophilized gE antigen with AS01B liquid adjuvant. Administer within 6 hours. | | Recombinant Subunit | Hepatitis B (Engerix-B, Recombivax HB) | IM | Refrigerator (2°C to 8°C) | Standard 3-dose series (0, 1, 6 months) using alum adjuvant. Expressed in yeast. | | Recombinant Subunit + CpG | Hepatitis B (Heplisav-B) | IM | Refrigerator (2°C to 8°C) | Accelerated 2-dose series (0, 1 month) utilizing CpG 1018 adjuvant for adults ≥18. | | Virus-Like Particle (VLP) | HPV 9-Valent (Gardasil 9) | IM | Refrigerator (2°C to 8°C) | 2-dose series if started at age 9–14 (0, 6–12 mo); 3-dose series if started at age 15+ (0, 1–2, 6 mo). Shake well. | | Toxoid Combinations | DTaP (Infanrix, Daptacel), Tdap (Boostrix, Adacel) | IM | Refrigerator (2°C to 8°C) | DTaP for children <7 years; Tdap booster for adolescents/adults and during every pregnancy at 27–36 weeks. | | Pure Polysaccharide | PPSV23 (Pneumovax 23) | IM or SC | Refrigerator (2°C to 8°C) | T-independent. Ineffective in children <2 years. 0.5 mL dose. | | Polysaccharide-Conjugate | PCV15 (Vaxneuvance), PCV20 (Prevnar 20) | IM | Refrigerator (2°C to 8°C) | T-dependent conjugate ($CRM_{197}$). Highly effective in infants and adults. Induces durable memory. | | mRNA (Lipid Nanoparticle) | COVID-19 mRNA (Comirnaty, Spikevax) | IM | Ultra-cold freezer or standard freezer / fridge | Contains LNP-encapsulated synthetic mRNA. Does not alter DNA. Follow manufacturer-specific thawing/puncture expiration rules. |
A community pharmacy is preparing an immunization clinic for a group of pediatric and adult patients. A 14-month-old child requires immunization against Streptococcus pneumoniae. Which immunological principle explains why a conjugate pneumococcal vaccine (such as PCV15 or PCV20) is indicated for this toddler rather than the pure polysaccharide pneumococcal vaccine (PPSV23)?
A patient receiving chemotherapy for lymphoma presents to the pharmacy requesting vaccines recommended prior to international travel. Which of the following vaccines is ABSOLUTELY CONTRAINDICATED in this patient due to their severe immunosuppression?
An adult patient aged 35 presents to the pharmacy to complete a Hepatitis B immunization series. The pharmacy stocks both Heplisav-B (HepB-CpG) and Engerix-B (HepB-alum). What is the primary clinical advantage of the CpG 1018 adjuvant in Heplisav-B compared to traditional aluminum hydroxide-adjuvanted Hepatitis B vaccines?