IAP Q & A on Vaccines and Vaccinology Abhay K Shah, Bakul Jayant Parekh, Srinivas G Kasi, Arun Wadhwa
INDEX
Page numbers followed by f refer to figure and t refer to table.
A
Accidental needle stick injury 159
Acellular pertussis 140
vaccine 138, 139, 140t
Acquired immunodeficiency syndrome 26, 351
Acute lower respiratory infections 197
Acute lung injury, transfusion related 114
Acute respiratory
distress syndrome 190
syndrome coronavirus 345
tract infection 191
Adenovirus
advantages of 364
vaccines 337
Adolescent Vaccination Program 304
Adrenaline 100
Adventitious viruses 364
Adverse Event Following Immunization 50, 72, 75f, 77f, 79, 94, 100, 206, 266, 382
types of 72
Advisory Committee on Immunization Practices 38, 146, 183, 197, 235, 251, 267, 295
Aedes aegypti mosquito 347
Alanine aminotransferase 311
Alcoholism 309
Allergens 3
Allergic disorders 368
Allogenic vaccines 369
Aluminum 328
hydroxide 136
oxide-based nanocarriers 330
phosphate 136
Alzheimer's disease 368, 373
Anaphylactic allergic reaction 200, 287
Anemia, severe 109
Antibody 3
affinity 16
dependent enhancement 357
functions of 8f
mediated organ transplant rejection 109
titers 364
Anti-cyclic citrullinated peptide 372
Anti-D immune globulins 107
Antigen 3
combination 20
dose of 19, 46
polysaccharide vaccine 215
presenting cells 8
Anti-hepatitis vaccine 226
Anti-pertussis toxin 302
Antirabies
immunoglobulin 394
vaccine 394
Antiretroviral therapy 371
Antiviral therapy 291
Anxiety 78
Asplenia 87
Asthma 309
Ataxia-telangiectasia 82
Atherosclerosis 368
Attack rate, secondary 27
Autism, association of 208
Autoimmune
diseases 372
disorders 110
lymphoproliferative disorder 109
Auxiliary nurse midwives 74
B
Bacillus-Calmette-Guérin 42, 119, 124, 339, 388, 389
reaction, classical 121
scar 124
severe complications of 121
vaccination
complications of 121
contraindications of 122
vaccine 119, 123, 373, 393
administration of 120
dosage of 120
role of 373
Bacteria 3
Bacterial infection, prevention of 113
B-cell activation 12
Bell's palsy 252
Bethesda system 240
Bioencapsulation 331
Blepharitis 290
Blindness 290
Blood
dyscrasias 170
transfusion 47
Bloody diarrhea 78
B-lymphocyte 5
deficiency disorders 82
Body mass index 191
Bordetella pertussis 302, 336
Botulism immunoglobulin 110
Bovine rotavirus pentavalent vaccine 164, 165
Breast cancers 369
Breastfeeding 169
Burkitt lymphoma 370
C
Canadian Adverse Events Following Immunization Surveillance System 95
Cancer
cells 369
clinical applications in 369
colorectal 369
Catch-up vaccination 167, 209
Cell-mediated immune response 122
Centers for Disease Control and Prevention 248, 277
Central Drugs Standard Control Organisation 359
Central nervous system 270
Cerebrospinal fluid 183
Cervical cancer 301
problem 241
Cervical intraepithelial neoplasia 240
Chickenpox 2, 228, 304, 312
vaccine 393
Chikungunya virus 350
Chlamydia 324
Chlorpheniramine 100
Cholera 26, 279, 317
vaccines 279, 281, 342, 393
Circumsporozoite protein 335
Cirrhosis 152, 311
Citrobacter freundii 217, 220
Clostridioides 113
Cochlear implants 183
Cold chain 54
elements of 55
equipment, specifications of 63t
management 54
representation of 54f
Colitis 113
Communicable diseases 378
Complement-mediated serum bactericidal activity 264
Complete blood count 114
Complex regional pain syndrome 252
Conjugate vaccine 179, 217, 264
advantage of 177
Convulsions 78
Corneal ulceration 290
Coronavirus disease 2019 5, 124
Cough 266
COVID-19 5, 124, 125
pandemic 365
risk of 355
vaccines 355, 357, 358, 360, 363, 365, 366
accelerated development 356f
efficacy of 366
technology 358t
CoWIN 367
Culex tritaeniorhynchus 270
Cytokines 326
Cytomegalovirus immune globulins 110
Cytotoxic cells 6
D
Dendritic cell 9
role of 10f
vaccines 369
Dengue
vaccine, status of 349
viruses 347349, 357
Deoxyribonucleic acid 151, 153, 239, 291, 324, 326, 345, 347, 369
vaccine 12, 326
basics of 325
Diabetes mellitus 155, 309
Diarrhea 266
severe 78
Diarrheal diseases 162
DiGeorge syndrome 82
Digital data loggers 65, 66f
Digital maximum-minimum thermometers 65, 66f
Diphtheria 30, 112, 302, 306
and tetanus 136
toxoids 102
clinical presentation 113
immunoglobulins 110
pertussis, and tetanus 135, 136, 377, 384, 389
vaccine for 135
pertussis, and vaccine
efficacy of 137
role of adjuvants in 136
tetanus and
acellular pertussis 42
whole-cell pertussis 42
tetanus toxoids 137
and whole-cell pertussis 136, 138, 139t
tetanus, and acellular pertussis 136, 138, 139t
toxoid 140, 146, 265
and acellular pertussis 42
nontoxic variety of 146
Disability-adjusted life years 25
Disodium phosphate anhydrous 294
Dog bite cases 257
Drug Controller General of India 248, 275
Dysgammaglobulinemia 170
E
Ebola virus 346, 346t, 356
disease 345
prevention of 345
infection 346
vaccine 346
Efficacy data
long-term 293t
short-term 293t
Egg allergy 201
Electronic vaccine intelligence network 68
Encephalitis 190, 208, 290
syndrome, acute 270
Endemic disease 26
Endocarditis 174
Enteroviral infections 109
Enzyme-linked immunosorbent assay 180, 280
Epinephrine 100
Epitope 3, 4f
Epizootic disease 26
Epstein-Barr virus infection 109, 370
Equine rabies immunoglobulin 257
Escherichia coli 341
F
Fabricius bursa 5, 45
Fainting 78
Fatty liver disease 311
Filamentous hemagglutinin 136, 140
Fimbrial hemagglutinin 136
Flavivirus 282
Fluorescent antibody 230
Follicular dendritic cells 16, 19
Follicular lymphoma 370
Food and Drug Administration 160, 334, 345
Freeze sensitive vaccines 56
Fungal ligand 5
G
Gastroenteritis 163, 164
Gastrointestinal loss 109
Gastrointestinal tract 171
Geometric mean
antibody titer 246
concentrations 178
titers 231, 274
Germinal center response 15f
Gliomas 369
Global Advisory Committee on Vaccine Safety 95, 252
Glycoconjugate 335
Glycoprotein enzyme-linked immunosorbent assay 230, 231
Graft-versus-host disease 85
Granulomatous disease, chronic 83
Guillain-Barré syndrome 74, 109, 195, 200, 208, 252, 266
H
H1N1
influenza 26, 356
strain 190, 191
H3N2 strain 191
Haemophilus influenzae 7, 31, 144, 178, 180, 213, 385
B
disease 148
infection 144
vaccine 146148, 248
Hand, foot and mouth disease 334
Hansenula polymorpha 153
Healthcare professionals, vaccinations of 311
Hearing loss 290
Heart
and light sensitive vaccines 56
disease
chronic 309
congenital 212
Helicobacter pylori 368
Hemagglutinin 189
Hematopoietic stem cell transplantation 81, 85t, 113, 158, 234
Hemoglobinopathies 183
Hemolytic anemia, autoimmune 109
Hemophagocytic lymphohistiocytosis 109
Hepatic transaminases 114
Hepatitis 150
A 15, 52, 86, 111, 222, 304
infection 222
vaccine 40, 41, 223226, 303
virus 35, 150, 304
autoimmune 311
B 15, 42, 52, 78, 84, 104, 150, 151, 304, 311
candidate vaccine 333
carriers 226
immunoglobulin 109, 158160
infections, chronic 371
problem 150
vaccine 88, 153, 154, 157, 159, 161, 328, 393
virus 150, 151, 151f, 152, 160, 333, 349, 372
C 311, 372
virus 150
D virus 150
E virus 150
infection 223
syndromes, acute 150
vaccine 46
Hepatocellular carcinoma 152
Herpes viruses 323
Herpes zoster 232, 290
history of 312
risk of 229
vaccination 310
Highly active antiretroviral therapy 157
Holoendemic disease 26
Human cytomegalovirus disease 340
Human diploid cell vaccine 256
Human immunodeficiency virus 87, 155, 170, 207, 234, 323, 333
immunization in 88t
infection 113, 121, 287, 315
vaccines, clinical trials for 352, 353
Human leukocyte antigen 373
Human papillomavirus 42, 239, 240, 302, 307, 323, 378
bivalent 243
infection 240, 242, 250
risk factors for 240
symptoms of 239
vaccine 239, 242, 244, 245, 249, 318, 393
contraindications for 252
effects of 250
use of 303
Human rabies immunoglobulin 257
Hyperendemic disease 26
Hyperhemolytic crisis 109
Hyperimmune globulins 107109
Hyperpyrexia 138
Hypertension 309, 318, 368
Hyperventilation 78
Hypogammaglobulinemia 113, 170
Hypotensive-hyporesponsive episodes 138
Hypothyroidism 318
Hypotonic-hyporesponsive episodes 49
I
Immune
deficiencies 110
dysfunction 323
globulins 108
response 17
conjugated vaccines 15
system, function of 3
thrombocytopenia 109
Immunity 3, 10f
active 11
adaptive 4f
cell-mediated 8, 121, 290, 325
cellular 8
herd 30, 30t
humoral 7
innate 4f
Immunization 3
anxiety-related reaction 72
documentation of 52
error-related reaction 72
schedule 146
technical support unit 68
Immunodeficiency
primary 107, 108
severe combined 121, 49, 170
Immunogenicity 208, 217
Immunoglobulin 3, 7, 107, 256
A 234
administration of 115t
G 151, 231, 234, 304
types of 7
use of 108
Immunosuppression 49
In vitro dendritic cell 325
Inactivated influenza vaccine 42, 195
contraindications for 196
efficacy of 196
side effects of 195
Inactivated polio vaccine 42389
fractional dose of 390f
Indian Academy of Pediatrics 38, 76, 146, 169, 195, 200, 235, 258
Indian Council of Medical Research 272
Indian Medical Association 76
Indian Neonatal Rotavirus Live Vaccine 165
Indian Rotavirus Strain Surveillance Network 163
Indirect fluorescent antibody 231
Infections 109
Inflammatory bowel disease 208
Inflammatory disorders 110
Influenza 189, 191, 192, 304, 312, 318, 323
complications of 190
disease burden of 190
management of 192
prevention of 192
severe 191
treatment of 192
type B 194
vaccine 192195, 200, 328, 394
composition of 193
types of 192
viruses 351
Integrated digital thermometers 65, 65f
International Certificate of Vaccination 285
International Health Regulations 285
Intradermal rabies vaccination 259
Intravenous immunoglobulin 230
G 107
doses of 110
use of 108
Invasive bacterial infection surveillance 175
Invasive pneumococcal disease 89, 174, 180
surveillance of 175
J
Japanese encephalitis 39, 270, 270, 304, 317, 389, 390f
control 271
disease burden of 271
prevention of 273
vaccine 270, 274, 276, 317, 394
Program 272
virus 270, 347
Joint pain 266
K
Kawasaki disease 109, 124
Killed oral whole-cell-bivalent vaccine 280, 281
Kolar strain vaccine, salient features of 275
L
Lactobacillus acidophilus 224
Lassa fever virus 345
Leukemia 170
acute lymphatic 236
chronic lymphocytic 109
Leukocyte adhesion deficiency 83
Live-attenuated hepatitis A vaccine 224
Live-attenuated influenza vaccine 198, 199
contraindications of 200
side effects of 199
Live-attenuated vaccines 11, 12
Live-attenuated yellow fever vaccine 276
Liver
cancer, primary 150
disease
alcoholic 311
chronic 226, 309
Low birth weight 159
Lung cancers 369
Lymphocyte antigen 370
Lymphoid tissue
gut-associated 331
nasal-associated 329
Lymphomas 170
Lyssavirus 254
M
Macrophage activation syndrome 109
Major histocompatibility complex 6
Malaria 26, 323, 368
vaccines 334, 335
Malignant cells 3
Mannide monooleate 328
Maternal antibodies 21
Measles 30, 384, 389
containing vaccine 211
postexposure prophylaxis 109
prevention 205
Measles and rubella 390f
vaccination campaigns 211
Measles, mumps, and rubella 42, 52, 208, 230, 304
and varicella 231
and varicella 318
vaccine 213
vaccine 36, 204, 206, 288, 316
contraindications for 207
immunogenicity of 207
Measles, pertussis, and diphtheria 301, 380
Measles, varicella containing vaccine 115t
Medical equipment 100
Medical termination of pregnancy 234
Melanoma 369
Membrane antigen 230
Memory B cells 16
Meningitis 174
belt 303
Meningococcal conjugate vaccine 264, 265, 315
Meningococcal polysaccharide vaccine 15, 265
Meningococcal serogroup B vaccine 268
Meningococcal vaccination 303
Meningococcal vaccine 263, 266, 304, 394
protection for 264
Mental retardation 212
Messenger ribonucleic acid 347
Microarray patch 331
Microneedle technologies 331
Mission Indradhanush 385
Monoclonal antibodies 107, 256
Mucosal vaccination 329
Mucosal vaccine delivery system, concept of 330
Multidose vial policy 68
Multifocal motor neuropathy 109
Multi-organ failure 190
Multiple myloma 108
Multiple sclerosis 233
Multistage vaccine 335
Mumps 30
Muscle 266
Myasthenia gravis 109
Mycobacterial disease 121
Mycobacterium
avium 122
indicus pranii 371
intracellulare 122
marinum 122
tuberculosis 119, 323, 339
vaccae 371
Myocarditis 190
Myositis 190
N
Nasopharyngeal carriage 174, 175
Nasopharyngitis 266
National Immunization Program 38, 124, 149, 153, 161, 168, 184, 263, 301, 306, 384, 386
National Immunization Schedule 387t
National Institute of Allergy and Infectious Diseases 347
National Regulatory Authority 93, 94, 360
National TB Control Program, revised 119
National Vector Borne Disease Control Program 272
Natural infection 152
Natural killer T cells 6
Natural varicella 229
Neisseria meningitides 146, 263, 312, 323
Neonatal alloimmune thrombocytopenia 109
Neonatal rotavirus vaccine 338
Neuraminidase 189
Neuritis 233
Neurologic disease 287
Neurological diseases 368
Neurological disorders 373
Neutralizing antibodies 349
Neutropenia, autoimmune 109
New tuberculosis vaccine 339
New vaccine
development 324
technologies 323
Nipah
glycoprotein 345
viral disease 347
virus 345, 347
disease, prevention of 347
Nonavalent Human papillomavirus vaccine 246
Noncommunicable diseases 368
Non-human adenovirus vectors 364
Noninvasive diseases 174
Nonpneumococcal conjugate vaccine 175
Nonsterile injection 73
Nonsteroidal anti-inflammatory drugs 284, 291
Novel virus 345
vaccine against 345
O
Obesity 368
Ocular palsy 290
Ocular zoster 290
Optimum immunization schedule 37
Oral cholera vaccine 279, 304, 336
Oral polio vaccine 127, 390f
birth dose of 130
characteristics of 126
monovalent 127
types of 126
Oral poliovirus vaccine 42, 126, 156, 169, 378
bivalent 127
Oral rehydration solution 162
Oral typhoid vaccine 216
Oral vaccine 280
Oseltamivir 192
Osteomyelitis 174
Otitis media, acute 180
P
Packing cold box 69
Pain relief 48
Paralytic polio, vaccine-associated 127
Paralytic poliomyelitis, vaccine associated 77
Parasites 3
Paratope 3, 4f
Paratyphoid
A vaccine 215
B vaccine 215
vaccine 215
development of 221, 342
Parvovirus infection, chronic 109
Passive immunity 11
Peramivir 192
Pertussis 30, 302, 307
toxin 136, 140
Phagocytic function disorders 83
Pichia pastoris 349
Plasmodium falciparum 335
Platelet alloimmunization 109
Pneumococcal bacteremia 174
Pneumococcal conjugate vaccine 42, 103, 174, 176, 177, 179, 181, 184, 389, 390, 394
efficacy of 180
Pneumococcal disease 174, 176
Pneumococcal infections 183
Pneumococcal polysaccharide vaccine 15, 176, 184, 394
Pneumococcal serotype 174
Pneumococcal vaccine 182184, 184t, 304
status of newer 187
types of 176
Pneumococcus 174
Pneumonia 174, 180, 290
Polio 30, 126, 384
endgame 129
eradication 127
status of 126
vaccine 40, 126, 316, 394
Polyepitope vaccine, development of 372
Polymerase chain reaction 135, 197, 232, 244
Polysaccharide 335
antigens 18
vaccine 14, 14f, 264, 315
efficacy of 264
Population level effects of vaccination, types of 29
Postexposure prophylaxis 111, 209, 337
Posthematopoietic cell transplantation 108
Postherpetic neuralgia 290
Postlicensure surveillance 94
Post-marketing surveillance, types of 95
Post-transfusion purpura 109
Post-transplant lymphoproliferative disorder 370
Postural orthostatic tachycardia syndrome 251
Postvaccination observation area, requirements of 99
Pregnancy 49
Prehematopoietic cell transplantation 108
Premature newborns, severe sepsis in 109
Programmatic vaccine deliveries 331
Prophylaxis, pre-exposure 111, 258, 337
Protection, serologic correlate of 218
Protein
antigens 18
loss, severe 109
Pseudomonas aeruginosa 217, 218
Purified chick embryo cell vaccine 256
Purified duck embryo vaccine 256
Pyrexia 266
Q
Quadrivalent influenza vaccine 194, 201
efficacy of 197
Quadrivalent meningococcal conjugate vaccine 103, 304
Quadrivalent vaccine 250
Quality-adjusted life years 25
Quillaja saponaria 294
R
Rabies 113, 254, 255, 312
immunoglobulins 110, 256
in dogs 255
transmit 254
vaccine 254, 259, 337
Randomized controlled trial 33, 217
Rapid schedule 154
Recombinant zoster vaccine 86
contraindications for 295
Recurrent infections 109
Re-exposure prophylaxis 256
Renal disease, chronic 156
Renal failure, chronic 155
Renal loss 109
Replacement phenomenon 175
Respiratory infection, acute 196
Respiratory syncytial virus 335
Resuscitation, cardiopulmonary 79
Reverse vaccinology 324
Rhabdomyolysis 190
Rhabdovirus 254
Rheumatoid arthritis 109
Ribonucleic acid 270, 324
vaccines 12, 324
Ringer's lactate 80
Rituximab therapy 84
Rotaviral diarrhea 167
Rotavirus 104, 162164, 167, 338
diarrhea 33
cause of 163
disease 162, 163
gastroenteritis, severe 166
infection 162, 163
strains of 163
vaccination 33
vaccine 42, 78, 162, 164, 165, 167171, 172t, 338, 390, 394
dose of 166, 169
Routine vaccination 276
Rubella 30, 113, 384, 389
control 204, 212
syndrome, congenital 207, 212, 213
vaccine 395
S
Saccharomyces cerevisiae 153
Salmonella
minnesota 294
paratyphi infection 342
typhi 218
Septicemia 174
Seroconversion 28
rate 218t
Serogroups 263
Seropositivity 28
Seroprotection 28
Serum
creatinine 114
glucose 114
Severe acute respiratory syndrome coronavirus 2 26, 124
Severe and serious adverse events following immunization 73
Sexual transmission 152
Sexually active 246
Shake test 67
negative 67f
Shigella vaccine 341
Shingles 290
prevention study 292
vaccine 307
Sickle-cell disease 183
Simple febrile seizures 138
Smallpox 30, 261
vaccine 90
Soft tissue infections 174
Solid organ transplant 81, 234
Spontaneous bacterial peritonitis 307
Squamous intraepithelial lesions 240
Standard immunoglobulins 107
Staphylococcus aureus 324, 342
Streptococcus pneumoniae 89, 177, 178, 323, 324
Strokes 290
Subcutaneous immunoglobulins 107
Subcutaneous immunotherapy 368
Subcutaneous vaccines 44
Sublingual immunotherapy 368
Supplemental immunization activity 128, 210
Swine flu 201
Synthetic peptide vaccines 324
Systemic inflammatory response 190
Systemic lupus erythematosus 109, 233
Systemic vascular inflammatory diseases 109
T
T cell
activation 12
dependent vaccines 15
independent immune response 13
types of 6
T helper cell 5, 122
T lymphocytes 5
Talimogene laherparepvec 369
Temperature monitoring devices 65
Termination of pregnancy 249
Tetanus 112, 302, 307
immunoglobulin 110
dose for 141t
prophylaxis 141
toxoid 140, 146, 301
doses of 142
Tetanus, diphtheria 42, 136, 306
and acellular pertussis 136
vaccine 395
vaccine 395
T-helper cells 6
Therapeutic tuberculosis vaccines 371
Therapeutic vaccines 368, 373
applications of 371
role of 368
scope of 373
status of 372
Thrombocytopenia 233
T-lymphocyte deficiency disorders 82
Toll-like receptors 9, 14
Toxic shock syndrome 109
Traditional vaccine development 356
Trained immunity 5
Transforming growth factor 6, 7
Travelers, vaccination for 272, 314
Treponema pallidum 108
Triplex vaccine 340
Trivalent influenza vaccines 194
Tuberculosis 26, 40, 119, 368
and pertussis 323
Tuberculous skin testing 123
Tumor cells 370
Typhoid
conjugate vaccine 215, 217, 304, 395
fever 215
polysaccharide vaccine 395
vaccine 41, 215, 221
developments in 342
types of 215
VI polysaccharide vaccine 216
U
United States Food and Drug Administration 274
Univalent varicella vaccine 86
Universal Immunization Program 168, 169, 210, 273, 384
vaccines in 388
Upper respiratory tract infection 266
Urine analysis 114
V
Vaccination 3, 284, 299
area, requirements of 99
clinics 98
documentation of 50, 51
procedure 43, 50
recommendations for 85t
records, nonavailability of 52
schedule 19, 37
Vaccine 17, 88
adjuvant-delivery system 331
administration 43, 379
schedule for 235, 390f
site of 389f
adverse effects of 281
adverse event reporting system 96, 251
candidates 358
carrier 70, 70f
concept, vector-based 327
delivery 331
derived poliovirus 128
development 351
documentation of 51
dose, part of 45
doses of 20t
effectiveness 29
efficacy 29, 310t, 348
failure 36
primary 36
secondary 36
hesitancy 379
immunogenicity of 28, 230
impact 30
in fridge, storage of 60, 61
plant-based 331
preventable diseases 306, 314
product-related reaction 72
quality defect-related reaction 72
recipient, documentation of 50
safety 92
network 95
sensitivity of 56t
simultaneous administration of 47
Sputnik V 359
storage of 57
temperature for 57t
subunit 11, 350
temporary storage of 69
types of 11, 264
combination 104
vial monitor 64
interpretation of 64f
Vaccine-preventable disease 301
disease epidemiology of 22
surveillance 33
Vaccinia immune globulins 110
Vaccinology
practice of 377
role in 327
Varicella 52, 228, 304, 312
epidemiology of 228
history of 312
infection 109
Varicella vaccination 233, 236, 237
adverse effects of 233
impact of 232
Varicella vaccine 228230
effect of 232
use of 235
Varicella zoster
immunoglobulin 110
virus 111, 231
Vasculitis 233
Vasovagal syncope 72
Vesicular stomatitis virus 327, 346
Vibrio cholerae 279
infection 317
Viral vector vaccines 337, 350, 351
Virosomes 328
Virus 3
infection 357
Viscerotropic disease 287
Vitamin E 328
Vomiting 78, 266
W
West Nile virus 347
vaccine 348t
Whole-cell inactivated typhoid 215
Whole-cell pertussis vaccine 102, 138
Wiskott-Aldrich syndrome 82
World Health Organization 39, 55, 126, 135, 144, 163, 193, 194, 204, 222, 225, 256, 263, 270, 271, 281
WRSS1 vaccine 341
X
X-linked agammaglobulinemia 82
Y
Yellow fever 90, 282284, 286, 287, 304
clinical features of 283
vaccination 286, 288
vaccine 82, 86, 282, 284, 286, 288, 315, 316, 347, 395
adverse effects of 287
virus, transmission cycles of 282f
Z
Zanamivir 192
Zika virus 347, 357
vaccine 347t
Zostavax 292
Zoster 290
vaccine 290, 292, 297, 307, 311
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Chapter Notes

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1Basic Vaccinology and General Considerations
  • Basic Immunology
    Abhay K Shah
  • Basic Epidemiology in Vaccinations
    Bhaskar Shenoy
  • Vaccination Schedules
    Suhas V Prabhu
  • General Immunization Practices
    Sanjay Srirampur
  • Documentation of Vaccination
    Chetan Trivedi
  • Cold Chain Management
    Sanjay Marathe, Srinivas G Kasi
  • Adverse Event following Immunization
    Arun Wadhwa
  • Vaccination in Special Situations
    Srinivas G Kasi
  • Vaccine Safety
    Srinivas G Kasi
  • Setting Up a Vaccination Clinic
    Vijay Kumar Guduru, Srinivas G Kasi
  • Combination Vaccines
    P Sivaraman
  • Immunoglobulins for Passive Protection against Vaccine-Preventable Diseases
    Raju C Shah, Pratima Shah2

Basic ImmunologyCHAPTER 1

Abhay K Shah
Q1. What is the function of immune system?
Ans. The immune system is an extremely important defense mechanism that can identify an invading organism, from outside the body (e.g., viruses, bacteria, parasites, allergens, etc.) or within the body, e.g., malignant cells, and destroy it.
Q2. What is immunity?
Ans. Immunity can be defined as a complex biological system endowed with the capacity to recognize and tolerate whatever belongs to the self, and to recognize and reject what is foreign (non-self).
Q3. What are antigens and antibodies?
Ans. A protein, toxin, or other substances of high molecular weight, to which the body reacts by producing antibodies and stimulates an immune response. Different organisms contain several different antigens.
Antibodies [Ab, immunoglobulins (Ig)] are protein molecules that bind specifically to a particular part of an antigen, called antigenic site or epitope. They are found in low levels in the blood and tissue fluids, including mucus secretions, saliva and breast milk. However, when an immune response is activated greater quantities are produced to specifically target the foreign material.
Q4. What is epitope and paratope?
Ans. An “epitope”, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a “paratope” (Fig. 1).
Q5. What is the difference between immunization and vaccination?
Ans. Immunization is the immune response to any administered antigen whereas vaccination is the immune response elicited in the body with the help of the vaccine.4
zoom view
Fig. 1: Epitope and paratope.
zoom view
Fig. 2: Differentiation between innate and adaptive immunity.
Q6. What are innate and adaptive of immune response elicited in body in response to an antigen?
Ans. Immunity may be broadly classified as innate and adaptive immunity (Fig. 2).
Innate immunity comes into play within hours of the entry of an infective agent. The components of the innate immune system comprise of epithelial and mucosal barriers (mechanical), the antibacterial chemicals in these barriers, phagocytes (neutrophils, macrophages and NK cells) as well as complement. It is not very specific as it is triggered by structures shared by different microbes instead of specific microbial antigens. There is no immune memory. It plays a very important role as it is the first line of defense. It is also the effector pathway of adaptive immunity.
The innate immune system triggers the development of adaptive immunity by presenting antigens to the B lymphocytes and T lymphocytes. Adaptive immunity takes time to develop. The two arms of adaptive immunity are humoral immunity (B lymphocyte mediated) and cell mediated immunity (T lymphocyte mediated). It has intense diversity and is capable of responding to millions of antigens and possesses immune memory. Adaptive immunity takes time to evolve and is pathogen specific.5
Q7. What is trained immunity?
Ans. The ability of the innate immune system to develop adaptive features and provide long-term protection against unrelated pathogens is term trained immunity. Epigenetic modification of various transcriptional pathways, as well as metabolic reprogramming of innate immune cells by both endogenous and exogenous stimuli, is the main driving force for trained immunity. Recent studies have revealed that innate immune cells, especially monocytes and macrophages, can develop adaptive features after adequate priming. Akin to adaptive immune response, trained innate immunity is associated with a heightened immune response to reinfections. In general, trained immunity is known to provide relatively short-term protection ranging from about 3 months to 1 year. Monocytes are very short-lived cells; however, the heightened secondary response can be spotted even several months after the primary stimulation. This shows that the immune memory is created at the level of progenitor cells, in the bone marrow.
A wide range of stimuli, such as beta-glucan (fungal ligand) and BCG (Bacillus Calmette-Guérin), are known to induce trained immunity. In humans, BCG vaccination-mediated non-specific protection against secondary infections is believed to be caused by trained immunity. Induction of trained immunity is considered to be a potential therapeutic strategy to manage various health conditions associated with immune system malfunctioning, such as cancer. Moreover, triggering trained immunity via live vaccines, such as BCG, measles, and oral polio vaccines, can be an effective approach in treating patients with severe infectious diseases, such as coronavirus disease 2019 (COVID-19). Long-term boosting of innate immune responses, also termed “trained immunity,” by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells.
Q8. What are B lymphocytes and T lymphocytes? What is their function?
Ans. B cells, also known as B lymphocytes, form the most important component of adaptive immunity (see Fig. 2). They provide humoral immunity by secreting antibodies. B-lymphocytes are produced in fetal liver and mature in the bone marrow in humans. In other species they mature in “Bursa of Fabricius” and hence named as B cells. B cells activated by the antigen present in the microbes and vaccines. These activated B cells are differentiated into antibody secreting plasma cells. For effective antibody B cells need help from T Helper cells.6
T cells or T lymphocytes are mediators of cell mediated immunity. They have a key importance in the immune system and are at the core of adaptive immunity. They originate in thymus and mature in periphery and get activated in spleen/nodes. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on the cell surface. T cell does not interact directly with the vaccine antigen unless presented by antigen presenting cells.
Q9. Which are different types of T cells?
Ans. They are as under:
  • CD4+ helper cells: CD4+ helper cells help in the maturation of B cells into plasma cells and memory B cells. They also help activate cytotoxic T cells and macrophages. They become activated when they are presented with peptide antigens by major histocompatibility complex (MHC) class II molecules, which are expressed on the surface of antigen presenting cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response.
  • CD8+ cytotoxic cells: CD8+ cytotoxic cells cause lysis of virus-infected and tumor cells. They are also involved in transplant rejection. These cells recognize their targets by binding to antigen associated with MHC class I molecules which are present on the surface of all nucleated cells. Cytotoxic cells secrete hole forming proteins called perforins for its cytolytic action.
  • Natural killer T cells: They bridge the adaptive immune system with the innate immune system. While most T cells function based on recognition of MHC class molecules, natural killer T cells are able to recognize other antigen classes. Once activated, they are also able to perform the same functions as CD4+ and CD8+ cells.
Q10. Describe clinical implications of Th1, Th2, Th17 and Treg immune responses.
Ans. T cells play a central role in the adaptive immune response. T-helper (Th) cells can be classified into Th1, Th2, Th17 and Tregs cells. Th1 cells produce interleukin (IL)-2 and interferon (IFN) γ and are involved in cellular immunity, which help to eradicate infections by intracellular microbes which include certain viruses, protozoans, and intracellular bacteria, such as the mycobacteria.
Th2 cells, which produce IL-4, IL-5 and IL-13, are involved in humoral immunity, mainly against extracellular microorganisms.
Th17 cells play a role in host defense against extracellular pathogens, particularly at the mucosal and epithelial barriers, e.g., B pertussis, but aberrant activation has been linked to the pathogenesis of various autoimmune diseases. TH17 cells arise when the cytokines IL-6 and transforming growth factor (TGF)-β predominate during naive CD4 T-cell activation.
Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting anti-tumour immunity. Suppression by inhibitory cytokines: interleukin-10 (IL-10), transforming growth factor-β (TGFβ) and the newly identified IL-35 are key mediators of TReg-cell function. Treg cells, which are CD4+/CD25+, regulate the functions of Th1, Th2 and Th17 cells.7
Clinical implications: In TB, T helper (Th)1 cytokines provide protection whereas Th2 and T regulatory (Treg) cytokines contribute to the pathogenesis and Th17 cytokines play a role in both protection and pathogenesis.
In respect to the type of cellular immunity, wP-containing vaccine induce a Th1 and Th17 skewed response whereas aP-containing vaccines mostly induce a Th2 skewed response.
Th1 responses have been traditionally elicited by live-attenuated, vector-based or Toll-like receptor ligand-adjuvanted formulations for optimal stimulation of the innate immune system and immunomodulation, while most of the present licensed alum-adjuvanted subunit vaccines fail to elicit Th1/Th17 immune responses.
Q11. What is humoral immunity?
Ans. Humoral immunity is mediated through B lymphocytes by secreting antibodies (immunoglobulins) that act by neutralization, complement activation or by promoting opsonophagocytosis, which results in early reduction of pathogen load and clearance of extracellular pathogens and their toxins. Some humoral antibodies prevent colonization, which is the first step in pathogenesis by encapsulated organisms such as Haemophilus influenzae type B (HIB), pneumococcal, meningococcal and non-capsulated organisms causing diphtheria and pertussis.
Q12. What are immunoglobulins? Which are different types of immunoglobulins? What is their role?
Ans. B cells have immunoglobulin surface receptors which bind with appropriate antigen that stimulates B cell to mature into antibody secreting plasma cells and generate immunoglobulins. Immunoglobulins are of different types (IgG, IgM, IgA, IgD and IgE) and they differ in their structure, half-life, site of action and mechanism of action. Scientists have identified nine chemically distinct classes of human immunoglobulins, four kinds of IgG and two kinds of IgA, plus IgM, IgE, and IgD. Immunoglobulins G, D, and E are similar in appearance.
The role of each type of immunoglobulin is as under (Fig. 3):
  1. IgG, the major immunoglobulin in the blood, is also able to enter tissue spaces, able to cross placenta, it works efficiently to coat microorganisms, speeding their destruction by other cells in the immune system.8
    zoom view
    Fig. 3: Functions of antibodies.
  2. IgD is almost exclusively found inserted into the membrane of B cells, where it somehow regulates the cell's activation.
  3. IgE is normally present in only trace amounts, but it is responsible for the symptoms of allergy.
  4. IgA guards the entrance to the body. It concentrates in body fluids such as tears, saliva, and secretions of the respiratory and gastrointestinal tracts.
  5. IgM usually combines in star-shaped clusters. It tends to remain in the bloodstream, where it is very effective in killing bacteria in early phase.
Q13. What is the main function of cell mediated or cellular immunity?
Ans. T cells are the effectors of cell mediated immunity (CMI). It is the principal defense mechanism against intracellular microbes. The T cell responses are more robust, long lasting and more cross protective than humoral responses hence modern vaccinology is being directed in this direction. The inherent T cell mediated immune regulatory mechanisms prevent any vaccines causing autoimmune diseases.
BCG is the only currently used human vaccine for which there is conclusive evidence that T cells are the main effectors.
Q14. What are antigen presenting cells (APC)?
Ans. Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.9
Q15. What are the dendritic cells?
Ans. Dendritic cells (DCs) are antigen-presenting cells (also known as accessory cells) of the mammalian immune system. They act as messengers between the innate and the adaptive immune systems. Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. At certain development stages they grow branched projections, the dendrites that give the cell its name as dendritic cell. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response.
Q16. What role do dendritic cells play in immunity?
Ans. Dendritic cells are the only cells, capable of activating naïve T cells and play a crucial role in the induction of T cell response. They capture antigen, process then into small peptides, display them through MHC molecules and provide costimulation signals to activate antigen-specific T cells.
Vaccine antigens are taken up by immature dendritic cells (DCs) activated by the local inflammation, which provides the signals required for their migration to draining lymph nodes. During this migration, DCs mature and their surface expression of molecules changes. DCs sense “danger signals” through their toll-like receptors and respond by a modulation of their surface or secreted molecules. Simultaneously, antigens are processed into small fragments and displayed at the cell surface in the grooves of MHC (HLA in humans) molecules. As a rule, MHC class I molecules present peptides from antigens that are produced within infected cells, whereas phagocytosed antigens are displayed on MHC class II molecules. Thus, mature DCs reaching the T cell zone of lymph nodes display MHC-peptide complexes and high levels of costimulation molecules at their surface.CD4+ T cells recognize antigenic peptides displayed by class II MHC molecules, whereas CD8+ T cells bind to class I MHC peptide complexes (Fig. 4).
Q17. What are toll-like receptors?
Ans. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Innate immunity is induced by exposure to evolutionarily conserved molecular structures termed pathogen-associated molecular patterns (PAMPs) that are expressed by a wide variety of infectious microorganisms. The recognition of PAMPs is mediated by pattern recognition receptors including TLRs, nod-like receptors and RIG-I-like receptors. Among them TLRs constitute one of the largest and most extensively studied classes of pattern recognition receptors. The innate immune response elicited by TLR activation is primarily characterized by the production of proinflammatory cytokines, chemokines, type I interferons (IFNs) and antimicrobial peptides. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity T cells, and B cells, and nonimmune cells. There are 13 TLRs, TLR 1 to TLR13, though the last three are not found in humans.10
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Fig. 4: Role of dendritic cells in immunity.
Q18. How do vaccines mediate protection?
Ans. Vaccines play a crucial role in prevention, elimination and eradication of vaccine preventable diseases. This is best achieved by immunization programs capable of inducing long-term protection. This can be achieved by the maintenance of antigen-specific immune effectors and/or by the induction of immune memory cells.
Most of the currently available vaccines provide protection through induction of B cells and production of antigen-specific antibodies. Antibodies either neutralize the antigen or promote opsonophagocytosis which results in early reduction of pathogen load and clearance of extracellular pathogens.11
The role of cell mediated immunity in currently used vaccines (that have T cell dependent antigens) is mainly by supporting antibody protection. Other less common mechanisms by which cell mediated immunity works is by cytotoxic CD8+ T lymphocytes (CTL) that may limit the spread of infectious agents by recognizing and killing infected cells or secreting specific antiviral cytokines. Cellular immunity is essential for clearance of intracellular pathogens. The generation and maintenance of both B and CD8+ T cell responses is supported by growth factors and signals provided by CD4+ T helper (Th) lymphocytes, which are commonly subdivided into T helper 1 (Th1) and T helper 2 (Th2) subtypes.
BCG is the only currently used human vaccine for which there is conclusive evidence that T cells are the main effectors. Another instance is measles vaccination at 6 months during outbreak. These infants fail to raise antibody responses because of immune immaturity and/or the residual presence of inhibitory maternal antibodies, but generate significant IFN-γ producing CD4+ T cells. As a result these children may remain susceptible to measles infection, but are protected against severe disease because of the viral clearance capacity of their vaccine-induced T cell effectors. Thus, prevention of infection may only be achieved by vaccine-induced antibodies, whereas disease attenuation and protection against complications may be supported by T cells even in the absence of specific antibodies.
Q19. Define active and passive immunity.
Ans. Active immunity is acquired through natural infection/immunization and is long lasting. Passive immunity is conferred by maternal antibodies or immunoglobulin/antitoxin sera preparations and is short lasting.
Q20. Which are main types of vaccines?
Ans. Vaccines may be broadly classified as follows:
  1. Live attenuated vaccines: BCG, oral polio, measles, MMR, chicken pox, Rota virus yellow fever, live influenza vaccine, live hepatitis A.
  2. Inactivated (Killed vaccines) may be:
    1. Whole cell inactivated: Whole Cell Pertussis vaccines, Rabies, IPV, Hepatitis A.
    2. Subunit vaccines: They differ from inactivated whole-cell vaccines, by containing only the antigenic parts which are necessary to elicit a protective immune response. They are as under—
      1. Protein vaccines:
        1. Inactivated toxins/toxoids (diphtheria/tetanus toxoids)
        2. Subunit vaccines: Acellular pertussis, HBV, some influenza.
      2. Polysaccharide vaccines:
        1. Pure polysaccharide: Comprising only of the polysaccharide—typhoid, PPPV, meningococcal
        2. Conjugated Hib, Typhoid, PCV Meningococcal—conjugation of the polysaccharide with a protein carrier (glycoconjugates) significantly improves the immune response.12
      3. Virus-like particle (VPL): HPV, Influenza
      4. DNA vaccines
      5. RNA vaccines.
Q21. What are live vaccines? How immunogenic are they?
Ans. Live attenuated vaccines (LAV) are derived from disease-causing pathogens (virus or bacteria) that have been attenuated under laboratory conditions. LAVs stimulate an excellent immune response as they mimic a natural infection. The vaccine virus/bacteria multiply and disseminate in multiple tissues and results in lymph node stimulation of dendritic cells at multiple sites. It also provides continual antigenic stimulation giving sufficient time for memory cell production. The activated DCs migrate towards the corresponding draining lymph nodes and launch multiple foci of T and B cell activation.
Q22. What are killed vaccines? How immunogenic are they?
Ans. Inactivated vaccines are made from microorganisms (viruses, bacteria, other organisms) that have been killed through physical or chemical processes. They can be whole or fractional subunit vaccines. Inactivated whole-cell vaccines are far less immunogenic as compared to live vaccines and the response may not be long lasting. Several doses of inactivated whole-cell vaccines may be required to evoke a sufficient immune response. In case of killed vaccines, there is only local and unilateral lymph node activation without associated dissemination and replication.
The immunogenicity of killed vaccine can be improved by various methods. Killed vaccines require adjuvants which improve the immune response by producing robust local inflammation and recruiting higher number of dendritic cells/monocytes to the injection site. Inactivated vaccines are more heat stable than live attenuated vaccines.
Q23. What are adjuvants?
Ans. Adjuvant is a substance that potentiates and/or modulates the immune responses to an antigen to improve their immunogenicity. They act by enhancing antigen presentation and/or by providing costimulation signals (immunomodulators). Aluminum salts are the most commonly used adjuvants in human vaccines. A toll-like receptors analog, named CpG ODNs, a new generation adjuvant, improves the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses:
  • Adjuvants help in the translocation of antigens to the lymph nodes where they can be recognized by T cells.
  • They provide physical protection to antigens which grants the antigen a prolonged delivery, providing additional time for upregulating the production of B and T cells needed for greater immunological memory in the adaptive immune response.13
  • They increase the capacity to cause local reactions at the injection site (during vaccination), inducing greater release of danger signals.
  • They induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of infection but also increase transcriptional events leading to a net increase of immune cells as a whole.
  • They are believed to increase the innate immune response to antigen by interacting with pattern recognition receptors (PRRs) on or within accessory cells.
Q24. Does the route of administration of vaccines matter with the type of vaccine? How?
Ans. The site and route of administration of killed vaccines is of great importance. For killed vaccines intramuscular route is preferred over the subcutaneous route. As the muscles are well-vascularized and has a large number of patrolling dendritic cells. Hence, the vaccines which are supposed to be given intramuscularly should not be given subcutaneously and even if administered inadvertently that dose should be discounted, e.g., Rabies vaccine, Hepatitis B vaccine.
Intradermal route recruits the abundant dendritic cells in the skin and offers the advantage of antigen sparing, early and effective protection but the GMTs are lower than that achieved with IM and may wane faster. Dendritic cells are in highest number in the skin and hence marked reduction (e.g., 10-fold) of the antigen dose in intradermal immunization, e.g., ARV, IPV.
Finally due to focal lymph node activation, multiple killed vaccines may be administered at different sites with little immunologic interference.
The site of administration is usually of little significance for live vaccines. Immunologic interference may occur with multiple live vaccines unless they are given on the same day or at least 4 weeks apart or by different routes.
Q25. What are the characteristics of T cell independent immune response? Which vaccines do exhibit such response?
Ans. T cell independent immune response is elicited by B cells only and has following characteristics:
  1. Only B cell response, T cell independent
  2. Poorly immunogenic below 2 years due to immaturity of the marginal zones
  3. Do not trigger GC activity
  4. Weaker and shorter immune response
  5. No induction of immune memory, hence no booster responses
  6. There is no local immunity as IgA are not produced
  7. Repeated doses lead to hypo responsiveness.
Bacterial (S. pneumoniae, N. meningitidis, H. influenzae, S. typhi) polysaccharide (PS) antigens exhibit T cell independent antigens.14
Q26. Describe the first steps after immunization.
Ans. Following vaccine injection, the vaccine antigens attract local and systemic dendritic cells, monocytes and neutrophils. Innate immune responses activate these cells by changing their surface receptors and migrate along lymphatic vessels, to the draining lymph nodes where the activation of T and B lymphocytes takes place. The type of response elicited will depend upon type of vaccine, its antigenic type and content and immune status of an individual. Vaccines that stimulate innate immunity effectively are better immunogens. This can be achieved by live vaccines, adjuvants, toll-like receptors (TLR) agonists, live vectors and DNA vaccines. Live vaccines are capable of activating innate immunity in a better way which is helpful for subsequent induction of adaptive immune effectors.
In the lymph nodes, the response to polysaccharide vaccines and protein/protein-conjugate vaccines are different.
Q27. What are the immune responses to polysaccharide vaccines?
Ans. On being released from the injection site they reach the marginal zone of the spleen/nodes and bind to the specific Ig surface receptors of B cells. In the absence of antigen-specific T cell help, B cells activate, proliferate and differentiate in plasma cells without undergoing affinity maturation in germinal centers. The antibody response sets in 2–4 weeks following immunization, is predominantly IgM with low titers of low affinity IgG. The half-life of the plasma cells is short and antibody titers decline rapidly. Additionally the PS antigens are unable to evoke an immune response in those aged less than 2 years. As PS antigens do not induce germinal centers, bona fide memory B cells are not elicited (Fig. 5). Consequently, subsequent re-exposure to the same PS results in a repeat primary response that follows the same kinetics in previously vaccinated as in naïve individuals.
Q28. What is hyporesponsiveness?
Ans. Revaccination with certain bacterial PS, of which Group C Meningococcus is a prototype, may even induce lower antibody responses than the first immunization, a phenomenon referred to as hyporesponsiveness. Due to this phenomenon, only a single booster of either Pneumococcal or Meningococcal polysaccharide vaccine is recommended even in patients who require lifelong protection.
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Fig. 5: Immune response to polysaccharide vaccines.
15
Q29. Which are characteristics of T cell dependent vaccines? Which vaccines do exhibit such response?
Ans.
  1. Consistently immunogenic in infants beyond 6 months
  2. Induces both T cell and B cell response
  3. Immune response is robust long lasting and with higher titers of IgG response
  4. High quality antibody
  5. Booster response with repeated doses
  6. No hyporesponsiveness.
Protein antigens which include pure proteins (Hepatitis B, Hepatitis A, HPV, Toxoids) or conjugation of PS antigens with a protein carrier (Hib, Pneumococcal, Meningococcal) are T cell dependent antigens.
Q30. What are the immune responses to protein and conjugated vaccines?
Ans. The immune enhancing effect of protein and of conjugate vaccines is assumed to result from an increase of carrier driven T-helper frequency and T-cell mediated costimulatory signals. Activation of germinal center (GC) is the key to such robust and long lasting immune response (Fig. 6).
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Fig. 6: The germinal center (GC) response.Source: Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L. Regulation of the germinal center response. Front Immunol. 2018;9:2469.
16
In response to a protein antigen reaching lymph nodes or spleen, B cells capable of binding to this antigen with their surface immunoglobulins undergo a brisk activation. In an extrafollicular reaction, B cells rapidly differentiate in plasma cells that produce low-affinity antibodies (of the IgM ± IgG/IgA isotypes) that appear at low levels in the serum within a few days after immunization (similar to PS antigens). Additionally, antigen-specific helper T cells that have been activated by antigen-bearing dendritic cells trigger some antigen-specific B cells to migrate toward follicular dendritic cells (FDCs) initiating the GC reaction. FDCs play an essential role in B cell responses: they attract antigen-specific B and T cells and capture/retain antigen for extended periods. B cells that are attracted by Ag-bearing FDCs become the founders of GCs. In GCs, B cells receive additional signals from follicular T cells and undergo massive clonal proliferation. This intense proliferation is associated to two major events: Ig class-switch from IgM toward IgG, IgA or IgE, and affinity maturation of the of B cells for their specific antigen which differentiate into plasma cells secreting large amounts of antigen-specific antibodies. At the end of the GC reaction, a few plasma cells exit nodes/spleen and migrate to survival niches mostly located in the bone marrow, where they survive through signals provided by supporting stromal cells.
The development of this GC reaction requires a couple of weeks, such that hypermutated IgG antibodies to protein vaccine antigens first appear in the blood 10–14 days after priming. It is the magnitude of GC responses, i.e., the quality of DC, B cell, Tfh cell and FDC interactions, which controls the intensity of B cell differentiation into plasma cells, and thus the peak of IgG vaccine antibody reached within 4–6 weeks after primary immunization.
Q31. What is antibody affinity and avidity?
Ans. Antibody affinity refers to the strength with which the epitope binds to an individual paratope (antigen-binding site) on the antibody. High affinity antibodies bind quickly to the antigen, permit greater sensitivity in assays and maintain this bond more readily under difficult conditions.
Antibody avidity describes the sum of the epitope specific affinities with which an antibody binds to a complex antigen.
Q32. What are memory B cells?
Ans. Memory B cells are those B lymphocytes that are generated in response to T-dependent antigens, during the GC reaction, in parallel to plasma cells. They persist there as resting cells until re-exposed to their specific antigens when they readily proliferate and differentiate into plasma cells, secreting large amounts of high-affinity antibodies that may be detected in the serum within a few days after boosting. Antigen-specific memory cells generated by primary immunization are much more numerous than naïve B cells initially capable of antigen recognition.17
Memory B cells do not produce antibodies, i.e., do not protect, unless re-exposure to antigen drives their differentiation into antibody producing plasma cells. This reactivation is a rapid process, such that booster responses are characterized by the rapid increase to higher titers of antibodies that have a higher affinity for antigen than antibodies generated during primary responses. The reactivation, proliferation and differentiation of memory B cells occur without requiring the induction and development of GC responses. This process is thus much more rapidly completed than that of primary responses.
Q33. Why do we need more than one dose, even for live vaccines?
Ans. The older concept that single dose of live vaccine induces life-long immunity is not true. The live vaccines induce an immune response similar to that seen with protein vaccines. However, live vaccines have limitations in the form of primary and secondary failures. Sometimes the take up of live vaccines is not 100% with the first dose (primary failure). Hence, more than 1 dose is recommended with these live vaccines. Once the vaccine has been taken up, immunity is robust and lifelong or at least for several decades. This is because of continuous replication of the organism that is a constant source of the antigen. The second dose of such live vaccine will take care for primary vaccine failures (no uptake of vaccine). Secondary vaccine failures are associated with decline in antibody titers with passage of time and here also second dose of live vaccine becomes necessary. The examples are varicella and mumps vaccines.
Q34. What is primary and secondary (booster) immune response?
Ans. When an antigen is introduced for the first time, the immune response starts after a lag of 10 days or so. This is called primary response. Such response is short-lived, has a lag period, mainly IgM type with low titers of antibodies. In primary immune response, the antigen exposure elicits an extrafollicular response that results in the rapid appearance of low IgG antibody titers. As B cells proliferate in GCs and differentiate into plasma cells, IgG antibody titers increase up to a peak value usually reached 4 weeks after immunization. The short-life span of these plasma cells results in a rapid decline of antibody titers, which eventually return to baseline levels 3.
Secondary immune responses start on subsequent exposure (booster) to the same antigen. There is no lag phase, response starts in less than 7 days, persists for a long time, mainly IgG type with high antibody titers. Booster exposure to antigen reactivates immune memory B cells and results in a rapid (<7 days) increase of IgG antibody titer by a rapid proliferation of memory B cells and their evolution into abundant antibody secreting plasma cells. Short-lived plasma cells maintain peak Ab levels during a few weeks, after which serum antibody titers decline initially with the same rapid kinetics as following primary immunization. Long-lived plasma cells that have reached survival niches in the bone marrow continue to produce antigen-specific antibodies, which then decline with slower kinetics. This generic pattern may not apply to live vaccines triggering long-term IgG antibodies for extended periods of time (Fig. 7).18
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Fig. 7: A schematic diagram showing a primary and secondary response.
Q35. Which are the determinants of intensity and duration of immune responses?
Ans. Both, primary and secondary immune responses after vaccination depend on various factors such as vaccine type, nature of antigen, vaccination schedule, genetic and environmental factors and age at immunization.
Vaccine Type
Broadly speaking live vaccines are superior (exception BCG, OPV) to protein antigens which in turn are superior to polysaccharide vaccines.
  • Live vs. inactivated: Higher intensity of innate responses, higher antigen content following replication and more prolonged antigen persistence generally result into higher antibodies (Ab) responses to live than inactivated vaccines.
  • Protein vs. polysaccharide: Recruitment of T cell help and induction of germinal centers (GCs) results into higher antibody responses to protein or glycoconjugate than to pure polysaccharide vaccines.
  • Adjuvants: Adjuvants improve immune responses to inactivated vaccines by either modulation of antigen delivery and persistence (depot or slow-release formulations) or enhancement of Th responses (immunomodulator) which may support or limit antibody responses.
Antigen Content
  • Polysaccharide antigens: Failure to induce GCs limit immunogenicity.
  • Protein antigens: Inclusion of epitopes readily recognized by B cells (B cell repertoire), inclusion of epitopes readily recognized by follicular helper T cells, elicitation of efficient follicular T cell help and the capacity of antigen to associate/persist in association to follicular dendritic cells (FDCs) result into higher antibody responses.19
  • Antigen dose: As a rule, higher antigen doses (e.g., Hepatitis B vaccine) increase the availability of antigen for B/T cell binding and activation, as well as for association with FDCs however there is a limiting dose for each.
Vaccination Schedule
The immune response improves with increasing number of doses and increased spaces between doses.
Other Factors
  • Age at immunization: Early life immune immaturity or age-associated immune senescence impairs immune responses to an administered vaccine.
  • Genetic factors: The capacity of antigen epitopes to associate to a large panel of MHC molecules increases the likelihood of responses in the population. MHC restriction may limit T cell responses. Gene polymorphisms in molecules critical for B and T cell activation/differentiation are likely to affect Ab responses. T cell responses differ markedly between individuals and populations because of genetic variability of MHC molecules (HLA A2).
  • Environmental factors: Mostly yet to be identified.
Q36. What is priming and boosting mechanism for killed vaccines?
Ans. The immune response improves with proper spacing of vaccine doses. Traditionally, “0-1-6” month schedule (prime and boost) is considered as a most immunogenic schedule than 6-10-14 week or 2,3,5 month or 2,4,6 month schedules for non-live T-cell dependent vaccines such as Hepatitis-B, vaccine. Here there is adequate time interval between first few doses for priming and inducing the immune responses and last dose that works as boosters. Since, affinity maturation of B-cells in GCs and formation of memory-B cells take at least 4–6 months, this schedule quite well fulfills these requirements.
More than one dose is needed for better induction and recruitment of more number of GCs in young age considering young age limitations of immune system. A 4 week minimal interval between primary doses avoids competition between successive waves of primary responses.
Q37. What should be the spacing between two or more vaccines?
Ans. The spacing between two or more live and/or killed vaccines is vaccines is given in Table 1.20
Table 1   Timing and minimal period of spacing between two doses of vaccines.
Antigen combination
Minimal interval between doses
2 or more inactivated antigens
None, can be administered simultaneously or at any interval between 2 doses
Inactivated and live antigens
None, can be administered simultaneously or at any interval between 2 doses
2 or more live
28 days minimum interval if not administered at the same visit
Q38. What is the importance of immune memory in immunization programs?
Ans. Immune memory allows one to complete an interrupted vaccine schedule without restarting the schedule. Immune memory is seen with live vaccines/protein antigens due to generation of memory B cells which are activated on repeat vaccination/natural exposure. Activation of immune memory and generation of protective antibodies usually takes 4–7 days. Diseases which have incubation periods shorter than this period such as Hib, tetanus, diphtheria and pertussis require regular boosters to maintain protective antibody levels. However, diseases such as Hepatitis A, Hepatitis B do not need regular boosters as the long incubation period of the disease allows for activation of immune memory cells.
Q39. What are limitations of immune responses during early life?
Ans. Transplacentally acquired maternal antibodies, and immaturity of immune system limit the immune responses during young age. IgG antibodies are actively transferred through the placenta, via the FcRn receptor, from the maternal to the fetal circulation. Upon immunization, maternal antibodies bind to their specific epitopes at the antigen surface, competing with infant B cells and thus limiting B cell activation, proliferation and differentiation. The inhibitory influence of maternal antibodies on infant B cell responses affects all vaccine types, although its influence is more marked for live attenuated viral vaccines that may be neutralized by even minute amounts of passive antibodies. Hence, antibody responses elicited in early life are short lasting. The extent and duration of the inhibitory influence of maternal antibodies increase with gestational age, e.g., with the amount of transferred immunoglobulins (Ig), and declines with postnatal age as maternal antibodies wane.
Early life immune responses are characterized by age-dependent limitations of the magnitude of responses to all vaccines. Antibody responses to most PS antigens are not elicited during the first 2 years of life, which is likely to reflect numerous factors including: the slow maturation of the spleen marginal zone; limited expression of CD21 on B cells; and limited availability of the complement factors. Although this may be circumvented in part by the use of glycoconjugate vaccines, even the most potent glycoconjugate vaccines elicit markedly lower primary IgG responses in young infants.21
Although maternal antibodies interfere with the induction of infant antibody responses, they may allow a certain degree of priming, i.e., of induction of memory B cells. This likely reflects the fact that limited amounts of unmasked vaccine antigens may be sufficient for priming of memory B cells but not for full-blown GC activation, although direct evidence is lacking.
Maternal antibodies inhibit only B cell induced antibodies responses but not T-cell response, which remain largely unaffected or even enhanced, e.g.,:
  1. BCG may be given as the maternal antibodies actually enhance T cell responses.
  2. OPV may be given as there are no maternal IgA in the gut to neutralize the virus.
  3. Measles vaccine if given at the age of 6 months (in an outbreak situation) may work by inducing T cell immunity.
Q40. How are these limitations of young age immunization overcome?
Ans. This issue can be addressed favorably to a certain extent by increasing the number of a vaccine doses for better induction, use of adjuvants to improve immunogenicity of vaccines, and by use of boosters at later age when immune system has shown more maturity than at the time of induction. Increasing the dose of vaccine antigen may also be sufficient to circumvent the inhibitory influence of maternal antibodies, as illustrated for hepatitis A or measles vaccines.
Q41. Why do we offer birth doses of BCG, OPV, HBV in spite of presence of maternal antibodies?
Ans.
  1. BCG can be given as maternal antibodies actually enhance T cell responses. (BCG is T cell response and not affected by circulating maternal antibodies)
  2. OPV may be given as there is no maternal IgA in the gut to neutralize the virus as maternal Ab are only IgG type. (Priming, so better seroconversion to subsequent doses)
  3. Birth dose of HBV acts as priming dose so that subsequent doses are capable of eliciting immune response even in presence of maternal antibodies. This is because maternal antibodies do not interfere with induction of memory B cells allowing certain degree of much needed priming. (Important for prevention of both vertical and horizontal transmission)22
Q42. Why do we practice early accelerated schedule of 6-10-14 weeks despite young age limitations on immunization schedules?
Ans. Immunization schedules, practiced in developed world, commencing at 2 months and having 2 months spacing between the doses are considered technically appropriate. However, we do not follow it in our country. Disease epidemiology of vaccine-preventable diseases (VPDs) in a country often determines a particular vaccination schedule. Since, majority of childhood infectious diseases cause morbidity and mortality at an early age in developing countries, there is need to protect the children at the earliest opportunity through immunizations. This is the reason why early, accelerated schedules are practiced in developing countries despite the known limitations of young age immunization. So for both, operational reasons and for early completion of immunization, the 6, 10, 14 week's schedule is chosen in developing countries. Such a schedule has shown to give adequate protection in recipients.
Q43. Why do we have different number of doses for different age groups for inactivated vaccines?
Ans. For killed vaccines such as DPT, Hib, Pneumococcal and Hep B which are administered as early as birth/6 weeks, the first dose acts only as a priming dose while subsequent doses provide an immune response even in presence of maternal antibodies. However a booster at 15–18 months is required for durable immunity. As the age of commencement of vaccination advances the number of doses reduces (2 doses at 6–12 months followed by a booster dose and 1–2 doses between 12 and 23 months for Hib and Pneumococcal vaccines).
Q44. Do we need a vaccine after getting recovered from a particular disease?
Ans. In general natural infection with viral illness provides very long lasting or life-long immunity. Hence, viral vaccines such as MMR, Varicella, etc., are not advised after such diseases. On the other hand bacterial illnesses do not impart such protection, justifying the need for vaccination, e.g., diphtheria, tetanus, typhoid.
SUGGESTED READING
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  1. Hong Kong Measles Vaccine Committee. Comparative trial of live attenuated measles vaccine in Hong Kong by intramuscular and intradermal injection. Bull World Health Organ. 1967;36:375–84.23
  1. Indian Academy of Pediatrics. Advanced Science of Vaccinology (IAP Module 2009). Mumbai: IAP;  2009.
  1. Indian Academy of Pediatrics. IAP Practical Vaccinology (module 2018). Mumbai: IAP;  2018.
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