# Lecture 20: Vaccines and Immunization

## Microbiology

---

## Learning Objectives

By the end of this lecture, students will be able to:

1. Define active and passive immunization and provide examples of each
2. Describe the major types of vaccines and the advantages and disadvantages of each
3. Explain the immunological basis of vaccination, including the role of memory cells
4. Describe the role of adjuvants in enhancing vaccine efficacy
5. Discuss herd immunity and its importance in public health
6. Outline the current recommended immunization schedules and the impact of vaccines on global health
7. Discuss emerging vaccine technologies including mRNA and viral vector platforms

---

## Lecture Content

### I. Principles of Immunization

**Immunization** is the process of inducing protective immunity against an infectious agent. **Active immunization** involves exposing the host to an antigen -- through either a vaccine or natural infection -- to stimulate the host's own immune system to produce antibodies and memory cells. Active immunization has a slower onset (weeks) but provides long-lasting protection that can persist for years or a lifetime.

**Passive immunization** involves the transfer of preformed antibodies from an immune individual to a non-immune individual. It provides immediate protection but is temporary, lasting only weeks to months as the transferred antibodies are catabolized. Examples include maternal IgG crossing the placenta, IgA in breast milk, administration of immune serum globulin (ISG), monoclonal antibodies such as palivizumab for RSV, and convalescent plasma. Passive immunization is used for post-exposure prophylaxis (rabies, hepatitis B, tetanus) and for protecting immunodeficient patients.

### II. Immunological Basis of Vaccination

Vaccines exploit the **primary immune response** to generate immunological memory. Upon vaccination, the antigen is processed by APCs, leading to T cell and B cell activation, clonal expansion, and the generation of effector cells that clear the antigen. Critically, **memory T and B cells** persist long after the antigen is eliminated. When the vaccinated individual subsequently encounters the natural pathogen, the rapid secondary response -- faster, of higher magnitude, and producing higher-affinity antibodies -- prevents disease.

**Correlates of protection** are the immune parameters associated with effective defense and vary by vaccine. For most vaccines, neutralizing antibody titers are the primary correlate. Cell-mediated immunity is important for tuberculosis and other intracellular pathogens. Mucosal IgA is relevant for mucosal pathogens. **Booster doses** re-expose the immune system to antigen, driving additional rounds of germinal center reactions, further affinity maturation, and replenishment of memory and effector cells.

### III. Types of Vaccines

#### A. Live Attenuated Vaccines

Live attenuated vaccines contain weakened forms of the pathogen that can replicate but cause little or no disease. Attenuation is achieved through serial passage in cell culture, animal passage, or genetic engineering with targeted gene deletions. The **advantages** of live attenuated vaccines include a strong immune response encompassing humoral, cell-mediated, and mucosal immunity; a single dose is often sufficient; and they closely mimic natural infection. The **disadvantages** include a small risk of reversion to virulence, contraindication in immunocompromised and pregnant individuals, and the need for cold chain storage. Examples include MMR (measles, mumps, rubella), oral polio vaccine (Sabin, OPV), varicella, rotavirus (RotaTeq, Rotarix), yellow fever (17D), BCG (tuberculosis), and live attenuated influenza vaccine (FluMist).

#### B. Inactivated (Killed) Vaccines

Inactivated vaccines contain pathogens killed by heat, formaldehyde, or beta-propiolactone, rendering them unable to replicate. Their **advantages** include no risk of reversion, greater stability, and safety for immunocompromised individuals. The **disadvantages** are a weaker immune response that is mainly humoral with little cell-mediated immunity, the frequent need for multiple doses and boosters, and limited induction of mucosal immunity. Examples include inactivated polio vaccine (Salk, IPV), rabies, hepatitis A, whole-cell pertussis (the older formulation), and inactivated influenza vaccine (injection).

#### C. Subunit, Recombinant, and Conjugate Vaccines

These vaccines contain only specific antigenic components rather than the whole organism. **Subunit vaccines** use purified proteins or polysaccharides, such as the acellular pertussis vaccine (containing pertussis toxoid, FHA, and pertactin) and the influenza vaccine (containing hemagglutinin and neuraminidase). **Recombinant protein vaccines** use antigens produced by recombinant DNA technology, including the hepatitis B vaccine (HBsAg expressed in yeast), the HPV vaccine (L1 capsid protein virus-like particles), and recombinant zoster vaccine (Shingrix, containing the gE glycoprotein with AS01B adjuvant).

**Conjugate vaccines** address a specific immunological challenge: polysaccharide antigens alone elicit a T-independent response that produces mainly IgM, with poor efficacy in children under two years of age. By covalently linking the polysaccharide to a protein carrier, conjugate vaccines convert this to a T-dependent response in which the protein carrier engages T helper cells, enabling class switching, affinity maturation, and memory formation. Examples include *Haemophilus influenzae* type b (Hib), pneumococcal conjugate vaccines (PCV13, PCV15, PCV20), and meningococcal conjugate vaccines (MenACWY). The overall **advantages** of subunit, recombinant, and conjugate vaccines are excellent safety profiles, well-defined antigens, and stability. Their **disadvantages** include the frequent need for adjuvants, multiple doses, boosters, and limited cell-mediated immunity.

#### D. Toxoid Vaccines

Toxoid vaccines contain bacterial toxins inactivated by treatment with formaldehyde. The inactivated toxins retain their immunogenicity but not their toxicity. The antibodies (antitoxin) they elicit neutralize the toxin upon natural exposure. Examples include tetanus toxoid and diphtheria toxoid, which are given in combination as DTaP or Tdap.

#### E. mRNA Vaccines

mRNA vaccines encode the target antigen in synthetic mRNA encapsulated in **lipid nanoparticles (LNPs)**. Upon injection, the mRNA is translated by host ribosomes in the cytoplasm, and the resulting antigen is produced, processed, and presented on both MHC I and MHC II molecules. The **advantages** of this platform include rapid development and manufacturing, strong humoral and cell-mediated responses, no risk of genomic integration (since mRNA does not enter the nucleus), and high adaptability to new variants. **Disadvantages** include the requirement for ultra-cold storage in some formulations, reactogenicity, and the fact that this is a relatively new platform with evolving long-term safety data. The first widely deployed examples were BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) for SARS-CoV-2. mRNA vaccines are currently in development for influenza, RSV, HIV, and cancer.

#### F. Viral Vector Vaccines

Viral vector vaccines use a harmless virus, typically an adenovirus or modified vaccinia Ankara (MVA), engineered to carry the gene encoding the target antigen. The vector infects cells, the antigen is expressed, and an immune response is triggered. **Advantages** include a strong immune response including cell-mediated immunity, and a single dose may suffice. **Disadvantages** include the possibility that pre-existing immunity to the vector can reduce efficacy, and rare adverse events such as vaccine-induced thrombotic thrombocytopenia have been observed with adenoviral vectors. Examples include Ad26.COV2.S (Johnson & Johnson) and ChAdOx1 (AstraZeneca) for SARS-CoV-2, and rVSV-ZEBOV for Ebola.

<image>A six-panel figure summarizing the major vaccine types. Panel A: Live attenuated -- weakened pathogen replicating in cells, stimulating both humoral and cell-mediated immunity; examples listed (MMR, OPV, varicella). Panel B: Inactivated -- killed pathogen, no replication, mainly humoral response; examples (IPV, rabies, hepatitis A). Panel C: Subunit/recombinant -- purified antigen (e.g., HBsAg VLP from recombinant yeast); adjuvant often needed. Panel D: Conjugate -- polysaccharide linked to protein carrier; T cell helping B cell in germinal center; examples (Hib, PCV). Panel E: mRNA -- lipid nanoparticle delivering mRNA into the cell; ribosome translates spike protein; protein displayed on cell surface and presented on MHC I and II. Panel F: Viral vector -- adenovirus carrying spike gene enters cell; gene expressed; protein triggers immune response. Each panel includes a pros/cons summary box.</image>

### IV. Adjuvants

**Adjuvants** are substances added to vaccines to enhance and modulate the immune response. They work through several mechanisms: creating a depot effect for slow antigen release, activating innate immune cells via PRRs, enhancing antigen uptake by APCs, and promoting cytokine production.

Common adjuvants include **aluminum salts (alum)**, the most widely used adjuvant, which creates a depot effect and produces a Th2-biased response. Alum is used in DTaP, hepatitis B, HPV, and pneumococcal vaccines. **AS01B** (MPL plus QS-21 in liposomes) generates strong Th1 and CD8+ responses and is used in Shingrix. **AS04** (alum plus MPL) is used in Cervarix (HPV). **MF59** (a squalene oil-in-water emulsion) enhances antigen uptake by APCs and is used in some influenza vaccines. **CpG oligonucleotides**, which act as TLR9 agonists, are used in Heplisav-B (hepatitis B). The **lipid nanoparticles** in mRNA vaccines function partly as adjuvants by activating innate immune pathways.

### V. Herd Immunity

When a sufficient proportion of the population is immune to a pathogen, its spread is significantly reduced, protecting those who cannot be vaccinated -- including infants, immunocompromised individuals, and the elderly. The **herd immunity threshold** depends on the basic reproduction number (R0) and is calculated as 1 - 1/R0. For measles, with an R0 of approximately 12--18, the threshold is approximately 92--95%. For polio, with an R0 of approximately 5--7, the threshold is approximately 80--86%. For SARS-CoV-2, threshold estimates have varied by variant, ranging from approximately 60% to 90%.

Herd immunity does **not** apply to non-communicable diseases such as tetanus, which is acquired from the soil. It can be achieved through natural infection or vaccination, though vaccination is by far the safer route.

<image>A three-panel illustration of herd immunity. Panel A: "No immunity" -- a population of figures where one infected individual (red) spreads disease to many susceptible individuals (blue), resulting in widespread infection. Panel B: "Some immunity, below threshold" -- some individuals are vaccinated (green) but not enough; infection still spreads substantially. Panel C: "Herd immunity achieved" -- most individuals are vaccinated (green); the few remaining susceptible individuals (blue, including icons representing an infant, elderly person, and immunocompromised patient) are protected because chains of transmission are broken. A formula box shows: herd immunity threshold = 1 - 1/R0, with examples for measles and polio.</image>

### VI. Vaccine Impact and Immunization Programs

Vaccines have had a transformative impact on global health. **Smallpox** was eradicated in 1980, the only human disease eliminated through vaccination. **Polio** is near eradication, with wild poliovirus remaining endemic in only Pakistan and Afghanistan in recent years. **Measles** deaths have been reduced by more than 95% globally since the introduction of vaccination campaigns.

The **childhood immunization schedule**, as recommended by the U.S. CDC and WHO Expanded Programme on Immunization, includes hepatitis B at birth; DTaP, IPV, Hib, PCV, rotavirus, and hepatitis B at 2, 4, and 6 months; MMR, varicella, hepatitis A, and PCV booster at 12--15 months; DTaP booster, IPV booster, MMR booster, and varicella booster at 4--6 years; and Tdap, HPV, and meningococcal conjugate vaccine at 11--12 years. Annual influenza vaccination is recommended for all ages. Adult immunizations include Tdap/Td boosters, zoster vaccine (age 50 and older), pneumococcal vaccine (age 65 and older), annual influenza, and COVID-19 vaccines. Globally, vaccines prevent an estimated 3.5--5 million deaths annually according to the WHO.

### VII. Challenges and Controversies

**Vaccine hesitancy**, fueled by misinformation (such as the debunked Wakefield study linking MMR to autism), remains a significant obstacle and was listed by the WHO as one of the top ten threats to global health in 2019. **Cold chain logistics** pose challenges for maintaining temperature requirements, particularly in low-resource settings. **Pathogen variability** complicates vaccine development: antigenic drift and shift in influenza require annual reformulation, and SARS-CoV-2 variants have necessitated updated boosters.

Some pathogens remain **difficult vaccine targets**: no highly effective vaccines yet exist for HIV, tuberculosis (beyond BCG), or a universal influenza vaccine. The RTS,S/Mosquirix malaria vaccine provides only partial protection. **Equity in vaccine access** continues to be a major concern, with significant disparities between high-income and low-income countries, as highlighted during the COVID-19 pandemic and addressed through initiatives such as COVAX.

### VIII. Future Directions

Several promising developments are on the horizon. A **universal influenza vaccine** targeting conserved epitopes such as the hemagglutinin stalk could eliminate the need for annual reformulation. The **mRNA platform** is being expanded for rapid adaptation to emerging pathogens and for personalized cancer vaccines based on tumor neoantigens. **Self-amplifying RNA (saRNA) vaccines** may require lower doses while producing stronger responses. **Thermostable formulations**, including microarray patches and lyophilized vaccines, could eliminate cold chain dependency. **Mucosal vaccines** delivered intranasally aim to induce secretory IgA at the portal of pathogen entry. **Broadly neutralizing antibody-based vaccine design**, guided by structural biology, is being pursued for challenging targets such as HIV.