Premed · Premed · Immunology
Lecture 29: Vaccines: Principles, Design, and Modern Platforms
Immunology
Learning Objectives
By the end of this lecture, students will be able to:
- Explain the immunological principles underlying vaccination (priming of adaptive immunity and memory)
- Describe the major types of traditional vaccines (live attenuated, inactivated, subunit, toxoid, conjugate)
- Explain modern vaccine platforms including mRNA vaccines, viral vector vaccines, and protein nanoparticle vaccines
- Describe the role of adjuvants in enhancing vaccine immunogenicity
- Discuss concepts of herd immunity, correlates of protection, and current challenges in vaccine development
Lecture Content
I. Principles of Vaccination
The fundamental goal of vaccination is to induce protective immunological memory without causing disease. Vaccines exploit the adaptive immune system's ability to generate long-lived plasma cells that sustain antibody production (serological memory), memory B cells that mount rapid antibody responses upon re-exposure, and memory T cells that provide rapid effector responses including CD8+ CTLs for intracellular pathogens and CD4+ help.
Correlates of protection are immune parameters associated with protection against a specific pathogen. For most vaccines, neutralizing antibody titers serve as the primary correlate. However, for some vaccines such as those targeting tuberculosis or malaria, T cell responses are critical. For mucosal pathogens, mucosal IgA may be the most relevant protective mechanism.
It is important to distinguish active from passive immunization. Active immunization involves administration of antigen (the vaccine), prompting the host to generate its own immune response and memory, providing long-lasting protection. Passive immunization involves administration of pre-formed antibodies, whether maternal IgG, IVIG, monoclonal antibodies, or convalescent plasma, providing immediate but temporary protection without generating memory.
II. Traditional Vaccine Types
Live attenuated vaccines contain weakened but replicating pathogen, produced by serial passage in cell culture, temperature-sensitive mutations, or genetic modification. Their advantages include a strong immune response that mimics natural infection, induction of both humoral and cellular immunity, often requiring only a single dose, and the ability to induce mucosal immunity when given orally or nasally. Their disadvantages include the risk of reversion to virulence, contraindication in immunocompromised patients, and requirements for cold chain storage. Examples include MMR (measles, mumps, rubella), varicella, oral polio (Sabin), yellow fever 17D, BCG, rotavirus, and live attenuated influenza nasal spray.
Inactivated (killed) vaccines use pathogen killed by heat, formaldehyde, or chemical treatment, rendering it unable to replicate. These are safer with no risk of reversion and can be used in immunocompromised patients. However, they produce a weaker immune response that is primarily humoral (IgG) with poor T cell activation, require multiple doses and boosters, and often need adjuvants. Examples include inactivated polio (Salk), injectable influenza, hepatitis A, and rabies vaccines.
Subunit and recombinant vaccines contain purified or recombinant protein antigens rather than whole pathogen. They are very safe with well-defined composition but require adjuvants, produce limited T cell responses, and need multiple doses. Examples include hepatitis B (recombinant HBsAg), HPV (virus-like particle-based using L1 capsid protein that self-assembles), acellular pertussis, and the Novavax COVID-19 spike protein nanoparticle vaccine.
Toxoid vaccines contain inactivated toxins treated with formaldehyde. They induce antibodies that neutralize the toxin (antitoxin antibodies). The classic examples are tetanus toxoid and diphtheria toxoid.
Conjugate vaccines address the challenge that polysaccharide capsule antigens are T-independent antigens that produce poor immune responses in children. By chemically conjugating the polysaccharide to a carrier protein such as tetanus toxoid or CRM197, the response is converted from T-independent to T-dependent, enabling T cell help, isotype switching, affinity maturation, and memory formation. This strategy is critical for protecting children under 2 years against encapsulated bacteria. Examples include Hib (Haemophilus influenzae type b), pneumococcal conjugate vaccines (PCV13/PCV15/PCV20), and meningococcal conjugate vaccines.
III. Modern Vaccine Platforms
mRNA vaccines deliver synthetic mRNA encoding the target antigen, such as the SARS-CoV-2 spike protein, encapsulated in lipid nanoparticles (LNPs). The mechanism proceeds through several steps. LNP-mRNA complexes are taken up by cells, especially dendritic cells and myocytes at the injection site. The mRNA is translated by host ribosomes to produce the antigen protein, which is expressed on the cell surface and/or secreted. Innate immune activation occurs as mRNA and LNP components stimulate innate sensors (TLR7/8 for single-stranded RNA), providing a strong adjuvant effect through type I interferon and pro-inflammatory cytokine production. Dendritic cells present antigen on both MHC class I (via cross-presentation) and MHC class II, activating CD8+ and CD4+ T cells respectively. Robust B cell responses follow, including germinal center reactions, high-affinity antibody production, and long-lived plasma cell generation.
The advantages of mRNA vaccines include rapid design and manufacturing (from sequence to vaccine in weeks), no DNA integration risk, strong immunogenicity, induction of both humoral and cellular immunity, and improved translation through nucleoside modifications such as N1-methylpseudouridine that reduce innate sensing. Disadvantages include cold chain requirements (ultra-cold for original formulations), reactogenicity from innate activation, and limited duration of expression. The principal examples are BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) for COVID-19.
Viral vector vaccines use a replication-deficient or replication-competent virus engineered to carry the gene encoding the target antigen. Common vectors include adenoviruses (human Ad5, Ad26; chimpanzee ChAdOx1), vesicular stomatitis virus (VSV), and modified vaccinia Ankara (MVA). The vector infects cells, the antigen gene is expressed, and the immune system responds to the encoded antigen. Advantages include strong immune responses that mimic viral infection and induction of both humoral and cellular immunity. Disadvantages include potential reduction in efficacy from pre-existing anti-vector immunity (especially to human Ad5) and rare adverse events such as vaccine-induced immune thrombocytopenia and thrombosis (VITT) observed with adenoviral COVID vaccines. Examples include ChAdOx1 nCoV-19 (AstraZeneca/Oxford), Ad26.COV2.S (J&J), and rVSV-ZEBOV for Ebola.
Protein nanoparticle and VLP vaccines use recombinant proteins assembled into nanoparticles or virus-like particles (VLPs). VLPs mimic viral structure but contain no genetic material, making them non-infectious. Their multivalent antigen display provides strong B cell activation by cross-linking B cell receptors. Examples include the HPV vaccine (Gardasil/Cervarix using L1 VLPs), HBV vaccine (HBsAg particles), and NVX-CoV2373 (Novavax spike protein nanoparticle with Matrix-M adjuvant).
<image>A comparison diagram of major vaccine platforms. Five columns showing: (1) Live attenuated -- a weakened virus particle replicating in a cell, producing viral proteins and triggering immune response; strong response indicated by multiple arrows; example: MMR. (2) Inactivated -- a killed virus particle being taken up by an APC; moderate antibody response shown; example: injectable flu. (3) mRNA -- a lipid nanoparticle (LNP) encapsulating mRNA strands, being taken up by a cell; the mRNA is translated into spike protein on ribosomes; the protein is displayed on the cell surface and also secreted; DCs cross-present to CD8+ T cells and present on MHC II to CD4+ T cells; strong antibody and T cell responses shown; example: Pfizer/Moderna COVID-19. (4) Viral vector -- an adenovirus vector carrying the gene for spike protein, infecting a cell; the gene is transcribed and translated, producing spike protein; similar immune activation pathway as mRNA vaccines; example: AstraZeneca, J&J. (5) Protein subunit/VLP -- recombinant protein nanoparticles with adjuvant being taken up by APCs; adjuvant (Matrix-M) activates innate immunity; strong antibody response shown; example: Novavax, HPV. A table below compares each platform on: antigen type, immune response (humoral/cellular), number of doses, cold chain requirements, and key advantages/disadvantages.</image>
IV. Adjuvants
Adjuvants are substances added to vaccines to enhance the immune response to the antigen. They work through several mechanisms: creating a depot effect that slows antigen release for prolonged immune stimulation, activating innate immune cells (dendritic cells and macrophages) to enhance antigen presentation, promoting cytokine production that directs the adaptive immune response, and enhancing antigen uptake by APCs.
Several adjuvants are in common clinical use. Alum (aluminum salts) is the most widely used adjuvant and promotes a Th2-biased response, creates a depot effect, and activates the NLRP3 inflammasome. MF59, a squalene oil-in-water emulsion, is used in enhanced influenza vaccines (Fluad) and promotes DC recruitment and antigen uptake. AS01, a combination of liposome, MPL, and QS-21, is used in Shingrix (herpes zoster) and the RTS,S malaria vaccine, producing strong Th1 and CD8+ responses. AS04 combines alum with MPL (a TLR4 agonist that promotes Th1 responses) and is used in Cervarix for HPV. Matrix-M is a saponin-based adjuvant used in the Novavax COVID-19 vaccine that provides potent immune stimulation. CpG oligodeoxynucleotides are TLR9 agonists used in Heplisav-B (HBV) that promote Th1 responses.
V. Herd Immunity and Vaccine Strategy
Herd immunity (community immunity) is achieved when a sufficient proportion of the population is immune, reducing transmission enough to protect unvaccinated individuals including infants and immunocompromised persons. The herd immunity threshold depends on the basic reproduction number (R0) of the pathogen, calculated as: threshold = 1 - 1/R0. For measles, with an R0 of approximately 15, approximately 93 to 95% vaccination coverage is needed. For wild-type COVID-19, with an R0 of 2 to 3, approximately 60 to 70% coverage was initially estimated, though higher thresholds apply for more transmissible variants.
Prime-boost strategies use an initial priming dose followed by booster doses to expand the memory pool and increase antibody affinity. Heterologous prime-boost approaches use different vaccine platforms for prime and boost (such as a viral vector prime followed by an mRNA boost) to elicit broader immune responses. Mucosal vaccines are needed to induce IgA at the portal of pathogen entry, since most current vaccines are parenteral and induce systemic IgG but provide limited mucosal protection.
VI. Challenges in Vaccine Development
Several obstacles remain in vaccine development. Antigenic variation in pathogens that mutate rapidly, such as influenza, HIV, and SARS-CoV-2 variants, means vaccines may not cover new strains, driving the need for updated or universal vaccines. Some pathogens practice immune evasion that defeats vaccine-induced immunity, as seen with malaria, tuberculosis, and HIV. For complex pathogens, identifying protective antigens presents a major challenge. Inducing mucosal immunity remains difficult with parenteral vaccines that fail to generate mucosal IgA. The duration of protection varies widely, with some vaccines like measles providing lifelong immunity while others require boosters, such as tetanus every 10 years, or wane significantly, as pertussis immunity does. Vaccine hesitancy fueled by misinformation and eroded public trust creates barriers to achieving herd immunity. Finally, global access and equity remain major challenges, with cold chain infrastructure, cost, and distribution logistics limiting vaccination in low-resource settings.
<image>A diagram illustrating the concept of herd immunity. Three scenarios are shown as communities of stick figures (circles representing individuals). Scenario 1 (No vaccination): A few infected individuals (red) spread disease widely; most individuals are susceptible (blue); extensive transmission chains shown as arrows between individuals, with many becoming infected. Scenario 2 (Partial vaccination, below herd immunity threshold): Some individuals are vaccinated/immune (green), but not enough to prevent spread. Infected individuals can still find susceptible contacts; moderate transmission persists. Vulnerable unvaccinated individuals (e.g., an infant, an immunocompromised person drawn distinctly) are at risk. Scenario 3 (Vaccination above herd immunity threshold): Most individuals are vaccinated/immune (green). The few infected individuals cannot sustain transmission because most of their contacts are immune. Transmission chains are broken (arrows blocked). Vulnerable unvaccinated individuals are protected by the immune majority surrounding them. The herd immunity formula (threshold = 1 - 1/R0) is shown with examples for measles and COVID-19.</image>
