FAQs on Vaccines and Immunization Practices Ajay Kalra, Vipin M Vashishtha
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Abscess 97
Acellular pertussis 43, 84, 246, 253
vaccine 228, 230, 238t, 242
Acquired immunodeficiency 370
syndrome 35, 191, 329, 364, 366, 476, 477
Activation-associated protein-1 664
Active bacterial core surveillance 373
Acute encephalitis syndrome 64, 67, 410, 411f
Acute flaccid
myelitis 219
paralysis 6467, 69, 71, 218, 219
Adaptive immune system 23
Adaptive immunity 4t
Adenocarcinoma in situ 451
Adhesin-based vaccine 591
Adjuvant 656
functions of 656
limitations of 666
vaccines, newer 656
Adolescent immunization 47, 677
Adolescent travellers, vaccines for 688t
Adolescent vaccination 677
Adult polio vaccination 212
Adverse drug reactions 95
Adverse effects following immunization 527
Adverse event following immunization 40, 93, 94t
types of 94
Advisory Committee on Immunization Practices 316, 317, 421, 456, 476, 522, 686
Advisory Committee on Vaccines 78
and Immunization Practices 45, 318, 376, 438, 477
Aedes aegypti 525, 620
Aerosol infection 390
Agammaglobulinemia 298
Alanine aminotransferase 600
Allergic disorders, vaccines against 635
Alleviate pain 48
Alpha-synuclein 650
Alzheimer's disease 643, 650
Ambiguous vaccine-derived poliovirus 203
American Academy of Pediatrics 329, 542
Amino acids 7
Anaphylaxis 453
Anesthesia, superficial 48
Angiotensin-converting enzyme 2 560
Animal exposure, management of 391t
Animal rabies
signs of 402
transmit 389
Antibody 607
affinity 7
containing products 55, 86, 326
dose of 87t
titers, correlation of 19f
vaccine-induced neutralizing 719
Anti-cyclic citrullinated peptide 651
Antigen
presenting cells 5, 631, 647, 649, 657
specific cells 11
specific immune effectors 11
tumor
associated 634, 648
specific 634
vaccine, liver-stage 513
Anti-inflammatory response 234
Anti-rabies
vaccination 392
vaccine 152, 393, 394, 399
types of 394
Antiretroviral therapy 191
Anti-tetanus prophylaxis 392
Antitubercular therapy 181
Anti-Vaccination Society 169
Anxiety-related reaction 97
Apical membrane antigen-1 vaccines 513
Arthus reaction 240, 249
Aseptic meningitis 275t
Aspiration 50
Asplenia, functional 86
Asthma 521
Atypical measles 259
Autoimmune diseases 650
Autopsy, conduction 99
Auxiliary nurse midwives 95
Avian influenza 464
Avidity 7
index 351
AYUSH doctor 155
B
B cells 5
B lymphocyte 24
primary 77
Bacillus calmette-guérin 12, 26, 43, 46, 59, 60, 82, 105, 111113, 161, 162, 178, 183186, 189, 190, 192, 194, 565, 687, 692, 724, 730
adenitis, management of 182b
immunization 193
role of 563
scar 180f
status of 177
strains 194
vaccination 180, 181f, 193, 196, 564t
vaccine 16, 41, 177, 178, 190192, 194, 195, 197, 262, 549
characteristics of 177
effects of 184
Bacterial colonization 11
Bacterial meningitis 68
Basic reproductive number 31
Basic transmission cycle 406
Bat-infested caves 390
B-cell lymphoma 643
Bell's palsy 219
Bioterrorism 215
Bivalent oral poliovirus vaccine 43, 200
Bleeding disorders 90
Blindness 259
Blood
stage vaccine 513
test 296
B-mannosylceramide 662
Bone marrow plasma cells 471
Booster doses 20
Bordetella 236
pertussis 224, 232, 236, 661
Bovine spongiform encephalopathy 134
C
Calicivirus 589, 590
infections 589
Calmette-guérin and rubella 51
Campaign vaccination 429
Campylobacter jejuni 588590
Cancer immune therapeutics 634
Candidate Shigella vaccines 593
Candidate vaccine, subunit 593
Capsular polysaccharide 483
Catch up immunization 91, 679, 683
schedule 46t
Catch-up vaccination 266, 679
Cell culture rabies vaccines 394
Cell culture-derived
influenza vaccines, advantages of 468
vaccines 468
Cell-based flu vaccine production 468
Cell-mediated immunity 3, 319, 662
role of 449
Cellular immune responses 657
Cellular immunity 657
Centers for Disease Control and Prevention 99, 318, 453, 590
Central Drugs Standard Control Organization 129
Cerebrospinal fluid 219
leaks 487
Cervarix 452t
Cervical cancer 446, 448
burden of 447
cause of 446
Cervical intraepithelial neoplasia 2 448
Chickenpox 327
vaccine 319, 684
Chikungunya virus 525, 617, 617f, 619, 619f, 620, 620f, 621, 622
biology of 617
development, vaccines for 624
fever
diagnosis of 621
treatment for 622
infection 620, 622, 624
phylogenetic 618
tree of 618f
prevention of 623
role of 623
vaccine 617, 622, 624
status of 624
Child and adolescent immunization schedule 79f
Childhood diarrhea 588b
Childhood vaccination schedule 269
Childhood vaccines 262, 399
Chimeric gene 639
Chimeric universal influenza vaccine 470
Chimeric vaccine 426, 639, 640
development of 426f
Chimpanzee adenovirus 602
Chinese vaccines, efficacy of 420
Cholera 491, 492, 679, 692, 703
epidemic 492
protective immunity in 493
toxin 491, 493
vaccine 491, 494, 696, 730, 731
role of 496
Chronic diseases 89
Clostridium perfringens 588
Cochlear implants 89
Cocooning 708
Cold chain 104, 105
and vaccine storage 104
breach 115
components of 105
Cold spots 109
Cold-sensitive vaccines 110
Combination vaccines 519, 520, 520t
advantages of 520
Common mucosal immune system 664
Complex regional pain syndrome 453
Congenital rubella syndrome 64, 162, 268, 678
Conjugate vaccines 10
Consumed milk 399
Contact immunity 32, 34
Control pertussis resurgence 247t
Cord antibodies levels 240f
Coronavirus 173, 556, 632, 643
vaccine 563
COVID 19 25, 36, 189, 556, 557, 559, 560, 563, 564t, 566, 691, 711
epidemic 121
infection 37, 122
pandemic 167
vaccines 556
COVID laboratory results, interpretation of 558t
Crohn's disease 650
Cryptosporidium parvum 589
Culex
mosquitoes 407
tritaeniorhynchus 405
Current immunization schedule 159
Cytokines 3
Cytomegalovirus 574, 577, 578, 703
candidate vaccines 578b
infection 574, 575
prevention of 581
vaccination 575
targets for 576b
vaccine 574, 576, 578t, 579, 580
development 577
Cytosine phosphate guanine 578
Cytotoxic T lymphocyte cell 8, 578, 609
D
Danger signals 5
Deadly disease 533
Dendritic cell 5, 6f, 24f, 651, 657
Dengue 498, 499, 499f, 678
cases, distribution of 499f
disease, burden of 498
fever 640
vaccine 498, 501, 503, 505, 507, 683
development of 502
virus 498, 506, 525, 641
immunity against 501
Dengvaxia 504
vaccine 504b
contraindications of 504
Deoxyribonucleic acid 11, 25, 185187, 281, 285, 287, 446, 468, 502, 561, 609, 629, 630, 630f, 631, 633, 635, 639
vaccine 513, 572, 605, 613, 629, 630
action of 631f
Dermonecrotic toxin 248
Diabetes mellitus
insulin-dependent 185
type 1 521, 651
Diarrhea 589
acute 588
Diarrheal disease 588, 589f
vaccines 588
Diarrheal episodes 589
Dimethyldioctadecylammonium 662
Diphtheria 35, 50, 54, 66, 6971, 717
acellular pertussis, and tetanus vaccine 151
and tetanus 105, 111113
toxoids 50, 59
pertussis tetanus 84
tetanus vaccine 59, 60
toxoid 12, 43, 253, 340
vaccine 34, 45
Diphtheria, pertussis 69
and tetanus 52, 69, 105, 111113, 151, 153, 418, 519, 692, 717
vaccine 178, 442
measles, mumps 34
Diphtheria, tetanus acellular, and pertussis 112
Diphtheria, tetanus and pertussis 60, 110
vaccines 22, 224
Diphtheria, tetanus toxoids
and pertussis 112
vaccines 249
Diphtheria, tetanus, and acellular pertussis 43, 46, 359, 519, 730
vaccine 227, 248, 687
Diphtheria, tetanus, and pertussis 43, 227, 254, 267, 515
vaccine, doses of 226f
Diphtheria, tetanus, and whole cell pertussis 43, 46, 519, 522, 687, 730
Disease estimation 29
Disease surveillance 62
District Immunization Officer 98
Dog bite 393
management of 707
Dog transmit rabies 398
Domestic refrigerator, types of 108
E
Ebola 35, 532
disease 533
kinds of 532
hemorrhagic fever 532
vaccines 532
virus 532, 534
disease 532, 533
Echovirus 9 219
Encapsulated bacteria 11
Encephalitis 259, 268, 390
Endgame strategy 213
Engerix-b 289
Entamoeba 118
Enterotoxigenic escherichia coli 591
Enteroviral vaccines 582
Enterovirus 582
vaccination for 582
Enterovirus A71
infections, complications of 582
vaccine, development of 584
Environmental mycobacteria 194
Environmental surveillance 74
Enzyme immunoassay 603
Enzyme-linked immunosorbent assay 533
technique 377
Epitope suppression 342
Equine rabies immunoglobulin 392
Equipment cleaners, types of 285
Escherichia coli 432, 458, 494, 589, 591, 597, 661, 665
Ethics Committee, responsibilities of 132
European Medicines Agency 515
Expanded Program on Immunization 12, 339, 414
F
Facial paralysis 219
Families vaccine hesitant 169
Febrile seizures
risk of 279, 384, 385, 515
simple 68
Fever, low-grade 169
Fine-needle aspiration cytology 181
Flu 462
causes of 462
danger signs of 464
vaccine 128, 465, 467b, 469, 478, 705, 716, 728
egg-based 468
Fluorescent-antibody-to-membrane-antigen 313
Food and drug administration 453, 468, 559
Furious rabies 390
G
Gardasil 452t
General vaccination 1
Genetic Engineering Approval Committee 134
Genetic vaccines 629
Genital warts 451
Geometric mean titer 306, 317, 450
Germinal centers 6
Giardia lamblia 118, 589
Glatiramer acetate 650
Glaxosmithkline 305, 436
tuberculosis vaccine 190
Glutamic acid dehydrogenase 651
Glycoconjugate vaccines 11
Glycoprotein B vaccine 579
Good clinical practice guidelines 132
Good manufacturing practice 417
Granulocyte-macrophage colony-stimulating factor 649
Guillain-Barré syndrome 249, 453, 466, 485, 590
H
H1N1 304
H3N2 475
Haemophilus B conjugate 358
Haemophilus influenzae 10, 63, 64, 67, 89, 110, 158, 204, 228, 298, 343, 357, 371, 692
Haemophilus influenzae type B 8, 12, 43, 46, 59, 60, 84, 112, 356, 359361, 374, 519, 687, 730
disease 356, 357
glycoconjugates 12
infection 357
meningitis 361
vaccination 360
vaccine 356, 356f, 357, 357t, 358361
Hand-foot-mouth disease 582, 583f
signs of 582
symptoms of 582
Hansenula polymorpha 458
Healthcare professionals, vaccines for 711
travel 719
Heat sensitive 111
Heat shock proteins 661
Helicobacter pylori 659
Hemagglutinin 462
Hematopoietic stem cell transplant 85
Hemolytic uremic syndrome 591
Heparan sulfate proteoglycans 449
Hepatitis 59
A2 729
birth dose 162
D 286
vaccine 308
inactivated 308
virus 304
Hepatitis A 12, 43, 302, 309, 519, 679, 692, 702, 703
infection 304, 307, 695
prevention of 89
vaccination 309
vaccine 82, 84, 161, 295, 302, 305, 307, 308, 681, 695
inactivated 308
live 306
live attenuated 305
side effects of 307
virus 302304
infection 308
vaccines 305t
Hepatitis B 12, 15, 16, 22, 43, 68, 76, 105, 111113, 152, 161, 165, 281, 285, 294, 498, 519, 679, 702, 703, 711, 724
acute 284, 285
birth dose 301
carriers 309
core 287
antibody 287
antigen 287
during pregnancy 707
E-antigen 282, 285287
immune globulin 713
immunoglobulin 286, 299
role of 298
infectivity of 711
laboratory nomenclature 287t
panel results 286
prevention of 89
schedule for 294
signs of 284
surface 287, 299
antibody 287, 713
antigen 285, 287, 294, 297, 299, 713
symptoms of 284
testing 286, 287t, 294
vaccination 179, 301
adverse effects of 291
vaccine 56, 84, 281, 286, 289, 290, 291, 295, 297, 298, 300, 308, 681, 712
against 45
dose of 292
efficacy of 290
monovalent 293
single antigen 296
types of 288
virus 8, 97, 281285, 285t, 287, 298, 299, 299t, 601, 659, 707
core protein 584
infection 282, 286, 296, 300, 308
infection, chronic 284, 286
infection, transmission of 282
maternal 288
prevalence of 281
role of 298
Hepatitis C 599
infection 599
vaccine 599, 600
development 601
virus 97, 609, 657
infection 600, 652
infection, epidemiology of 599
Hepatitis E 703
chronic 594
infection, prevalence of 594
vaccines 594
virus 594
combination vaccine of 597
components of 595
infection 594
Herd immunity 32, 35
Herd protection 33, 34
Herpes simplex virus 26, 188, 657, 703
Herpes zoster 318, 320
Heterologous immune 27
Hip dysplasia 54
Histocompatibility complex, major 5, 633, 643
Hodgkin disease 370
Human coronavirus 563
Human cytomegalovirus 578
Human enterovirus 582
Human immunodeficiency virus 35, 97, 190, 191, 201, 206, 262, 329, 366, 380, 441, 454, 477, 489, 553, 559, 568, 568f, 569, 601, 605, 643, 657
biology of 568
infection 291, 316, 361, 370, 504, 653
vaccine 568, 569
development of 570
Human interleukin, recombinant 578
Human leukocyte antigen 5, 607, 609
Human papillomavirus 14, 43, 84, 161, 446450, 519, 576, 585, 652, 659, 678, 687, 692, 702, 704, 730
diseases 454
infection 448
vaccination 455
during pregnancy 704
protection after 459
vaccine 446, 450t, 453, 454, 456, 457459, 507, 679
Human rabies immunoglobulin 392
Human-to-human transmission 406
Humoral immunity 657
Hyperimmunoglobulins 54
Hyperventilation 97
Hypocalcemic seizures 252
Hypoglycaemia, severe 185
I
Ibuprofen 22
Ice-lined refrigerator 111, 112
Ideal adjuvant, features of 657
Idiopathic thrombocytopenic purpura 326
Immune globulin 310
Immune memory 23
Immune response
primary 18
secondary 18
Immune system 4, 6, 23
maturation of 350
Immunity
active 120
evidence of 319
nonspecific 4
specific 4
types of 119
vaccine-induced 233, 449
Immunization 60, 81
adverse effect of 75
after pregnancy 702t
anxiety-related reaction 94
before pregnancy 702t
before travel 691
maternal 237, 700
practices 264
primary 161, 254, 423
program 105
purpose of 39
record 156
regular 155
schedule 39, 42, 162
Immunized child 161
Immunizing pregnant women 90
Immunocompromised children 298
Immunocompromised conditions, types of 77
Immunodeficiency, severe combined 441
Immunogenicity 291, 417
data, long-term 351t
Immunoglobulin
A 12, 18
G 12, 18, 273, 316, 335, 558, 559
M 18, 287, 482, 558, 559
Immunosuppressive agents, categories of 81
Inactivated vaccine, trivalent 377, 466
Inconsolable crying 250
Indian Academy of Pediatrics 153, 267, 306, 395, 471, 486, 727, 732
Indian Council of Medical Research 145, 566
Infant antibodies 700f
Infant pertussis
immunization 242
vaccination 243
Infection
bite by rabid dog, risk of 403
chronic 303
control 120
Infection and prevention of disease, prevention of 550
Infectious disease 31, 35, 35t, 36t, 118, 119, 121, 122
control and eradication of 118
incidence of 121
Influence vaccine hesitancy 168
Influenza 12, 35, 462, 679, 714
A 466, 715
viruses 474, 475
B 464, 474, 715
victoria lineage 466
complications of 463
intranasal 12
surveillance 464
symptoms of 463
vaccination 472, 479
varicella and zoster infection 78
virosomes 305
virus 462, 463, 463f, 469
types of 462
Influenza vaccine 128, 377, 462, 467, 471, 473, 476, 477, 680, 715, 728, 730
coverage of 471
inactivated 468, 472, 475, 477
live attenuated 59, 466, 468, 702, 707
production 468fc
recombinant 476
trivalent 705
types of 466
Injectable polio 156
Innate and adaptive immunity 3, 4f
Innate cells 24
Innate immunity 4t, 183
Integrated Disease Surveillance Program 63, 100
Integrated vector management, role of 623
Interferon-gamma 8, 347, 635
Intravenous immunoglobulin 54, 327, 328
Invasive bacterial infections surveillance 356
Invasive cervical carcinoma 448
Invasive pneumococcal disease 363, 370, 373, 380
Ipsilateral inguinal lymphadenopathy 192
Isothermic cold boxes 114
J
Japanese B encephalitis 688
Japanese encephalitis 67, 68, 99, 158, 405, 408, 409, 410f, 411f, 498, 679, 692, 703, 724
disease 405
epidemiology of 408, 409
risk of 408f, 430
transmitted 405
virus 405, 406, 639
genotypes of 427
transmission, rethinking 407f
Japanese encephalitis vaccine 158, 414, 414b, 415t, 420, 429, 430, 431b, 681, 696, 697, 697b, 719, 729731
cost-effective 430
current status of 414
dose of 165, 719
inactivated 428b
live attenuated 414
new generation of 431
recombinant 432
types of 430b
use of 428b
Jeryl-Lynn strain 275
K
Kidney diseases, chronic 89
Killed oral vaccine 591
L
Lapsed immunization 91
Latent tuberculosis infection 549
Leishmaniasis 642
Leningrad-3 strain 275
Leukemia 328
Leukocyte migration inhibition test 179
Linked-epitope suppression 236
Lipoidal biocarriers 572
Live viral vaccine 42f, 529
measles vaccine 261
Liver disease, chronic 89, 309
Low birth weight
babies 209
infants 293
Lower respiratory infection, acute 541
Lymph node 181
activation 13
Lymphocytic choriomeningitis virus 578
Lymphoid tissue, mucosa-associated 662
Lymphoreticular tissue, nasopharyngeal-associated 664
L-zagreb strain 275
M
Macrophages 3
Malaria 509
control and prevention 510
Elimination Program 509
elimination, technical strategy for 509
Policy Advisory Committee 515
transmission 512
Malaria vaccine 509, 510
development 511, 512
explored for 512b
Implementation Programme 517
initiative 511
timeline of 511t
types of 512
Master cell bank 134
Maternal antibody 11, 16, 42f
concentrations 246
influence 16, 41
Measles 12, 35, 111
hepatitis, and varicella 11
modified 259
risk for 716
vaccines against 45
virus, strains of 261
Measles and rubella 66, 69, 71, 72fc, 724
elimination 68
initiative 268
surveillance project 73fc
vaccination program 263
vaccine 152, 274
Measles vaccination 262
adverse reactions of 261
contraindications of 261
regular 260
schedule of 261
Measles vaccine 162, 259261, 263
role of 263
Measles, mumps and rubella 55, 111, 152, 261, 264, 266, 269, 271274, 276278, 315, 683, 716, 730
and varicella 317, 519, 521, 730
vaccines 279
dose of 274, 269, 271
third dose 269
vaccination 272
vaccine 43, 46, 59, 60, 266, 267, 270t, 271, 273, 274, 276278, 683, 693, 702
doses of 272, 276
Membrane vesicles 352, 483, 593, 642
Memory B cell 15, 236, 449
hallmarks of 19
Menacwy vaccines 489
Meningitis 268
Meningococcal conjugate 12
vaccine 481, 482, 576, 692
Meningococcal disease 642, 703
Meningococcal polysaccharide vaccine 482
Meningococcal recombinant protein vaccines 481
Meningococcal serogroup B vaccines 489
Meningococcal vaccination 487
Meningococcal vaccine 11, 481, 487, 488, 680, 688, 694, 718, 730, 731
Meningococci, types of 481
Meningococcus 693
Meningoencephalitis 219
Merozoite surface protein-1 vaccines 513
Messenger ribonucleic acid 468, 561, 631, 632
vaccines 561
types of 561
Metered-dose inhaler 330
Micro-ribonucleic acid 187
Middle ear infection 259
Middle east respiratory syndrome 632
coronavirus 643
Miliary tuberculosis 177
Ministry of Health and Family Welfare 145
Monocytes 3, 13
epigenetic reprogramming of 187f
Moraxella catarrhalis 371
Mouse brain 414
Mucosal adjuvants 664
Mucosal immunity 213, 572
Multiepitope fusion vaccine 591
Multiple sclerosis 453, 650
Multiple vaccines, administration of 56b
Multivalent combination vaccines 336
Mumps 12, 35, 37, 269, 678
containing vaccine 268f
infection 273
measles rubella 82
vaccine 275t, 683
virus 717
Muramyl dipeptide 665
Mutants matter 285
Mutational antigens 634
Mycobacterium
avium 194
bovis 196
intracellulare 194
marinum 194
tuberculosis 11, 25, 549
infection 183
N
Nasal mucosa 3
Nasopharyngeal swabs 558
National Drug Regulatory Authority 101
National Immunization Program 164, 229, 373, 385, 436
National Immunization Schedule 44t, 158, 161, 163, 206, 723
National Immunization Technical Advisory Group 145
National Institute for Communicable Diseases 399
National Institute of Virology 67
National Institutes of Health 444
National Technical Advisory Group on Immunization 147, 149
National Vector Borne Disease Control Programme 410, 509
Neisseria meningitidis 10, 89, 642, 718
Neoantigens 648
Neomycin 48
Neonatal immune responses 16
Neonatal sepsis, severe 184
Nephrotic syndrome 330, 370
Nerve tissue vaccine 393
Neuraminidase 462
Neutrophils 3
New pertussis vaccines 247
New vaccine, approval of 136
Noninvasive pneumococcal disease 374
Nonlive vaccines 6
Nonsterile injection, causes of 97b
Nonsteroidal anti-inflammatory drugs 621
Nontuberculous mycobacteria 194
Norovirus 35, 590
Norwalk virus 589
Novel antigen candidate vaccines 593
Novel oral polio vaccine type 2 220
Nucleic acid vaccines 560
Nucleocapsid protein 559
O
Onchocerca volvulus 664
Optimal immunization schedules 39
Oral cholera vaccine 495, 688
Oral polio vaccine 16, 82, 156, 178, 182, 199, 200, 201, 207217, 418, 439, 521, 724, 730
cessation 215
contraindications of 201
doses of 8, 208, 211
monovalent 200
side effects of 201
stockpiles 221
trivalent 199
types of 199
Oral poliovirus vaccine 46, 60, 105, 112, 113
Oral rehydration solution 442
Oral sex 284
Orally administered vaccines 49
Orchitis 268
Organ transplants 390
Orthomyxoviridae virus 462
Otitis media 371
acute 363, 371
P
Pancreatitis 268
Paracetamol 22
Paralytic poliomyelitis, vaccine-associated 201, 202, 210
Paralytic rabies 390
Parasitic infection 195
Paratope 7
Paratyphoid fevers 334f
Parenteral vaccines, administration of 49
Parkinson's disease 650
Passive neonatal immunity 703
Passively acquired immunity 119
Pathogen-associated molecular patterns 8
Pediatric dengue vaccines, development of 502
Penta vaccine, dose of 97
Pentamer protein complex 577
Pentameric complex 578
Pentameric vaccines, soluble 579
Pentavalent vaccine 162
Pentaxim 228
Peptide vaccines 602, 651
Pertussis 35, 66, 6971, 239
booster 54
disease 234
epidemiology of 224
resurgence 246
samples 71
toxin 248
toxoid 253
vaccination 230, 249
vaccine 227, 237, 238t, 247, 251t
against 45
doses of 252
live attenuated 248
Pet dog, vaccinated 398
Peyer's patches 664
Phagocytic function disorders, primary 77
Pichia pastoris 458
Pivotal trials 423
Placental transfer, percentage of 703f
Plasma cells, long-lived 19
Plasmodium falciparum 513
circumsporozoite protein 512
bacteria vaccines 513
Pneumococcal conjugates 12
vaccine 20, 43, 158, 243, 363, 367, 370, 371, 373377, 379, 380, 383f, 385, 693, 705, 724, 725, 730
against pneumonia 372
Pneumococcal disease 364
high risk for 380t
Pneumococcal pneumonia and mortality, burden of 365
Pneumococcal polysaccharide vaccine 20, 367, 378, 679, 681, 730
Pneumococcal vaccine 84, 158, 680
candidates 386
Pneumococcus 693
serotypes of 366
Pneumonia 259, 364f
episodes, severe 365f
rotavirus, measles, mumps and rubella 692
Polio 11, 35, 692, 718
campaign 212
eliminated 163
free status 212
global eradication of 214
immunization 206, 207, 209, 218
like syndrome 219
outbreak simulation exercise 219
sabin 12
salk 12
transition 220
vaccination 206, 209
schedule 207t
status of 718
vaccine 41, 102, 199, 204206, 216, 399, 697
against 45
inactivated 34, 43, 84, 97, 112, 153, 161, 199, 203, 205, 207213, 692, 724, 730
sabin inactivated 216, 217
schedule 207
vaccination 206
Poliomyelitis 199
clinical spectrum of 199t
Poliovirus 76
vaccine
derived 65, 202, 203, 210
inactivated 46, 519, 522, 687
Polymerase chain reaction 558
real-time 67
Polyradiculitis 268
Polyribosylribitol phosphate-outer membrane protein 358
Polysaccharide 12, 339
conjugate vaccines 592
vaccine 10, 14, 335
unconjugated 481, 482
Population for vaccination 120
Positive rubella titer 272
Postexposure prophylaxis 271, 299t, 307, 309, 310, 396, 397t, 707
Postexposure vaccination 712
Postpolio eradication strategy 214
Postural orthostatic tachycardia syndrome 453
Post-vaccination
blood test 284
serologic testing 714fc
Pre-erythrocytic vaccine 512
Pre-exposure prophylaxis 394, 688
against rabies 396
Pre-exposure vaccination, schedule of 395
Pregnant woman traveler 694
Preservatives, roles of 48
Pretransplant 85
Primary complement deficiency 77
Prophylactic B cell combined vaccines 602
Prophylactic paracetamol 23
Prophylactic T cell combined vaccines 602
Prophylactic vaccine 608t
candidates 608
Prostatic acid phosphatase 649
Protein
polysaccharide conjugate vaccine 339, 339t
subunit 571
vaccines 483
Pseudomonas aeruginosa 340
Psoriasis 650
Pulmonary tuberculosis 177, 183, 549
Pulse
Immunization Program 218
oral polio vaccine 218
polio immunization 218
Purified chick embryo cell vaccine 394
Purified formalin inactivated vaccine 615
Purified protein derivative 179
Purified vero cell rabies vaccine 394
Q
Quadrivalent conjugate 702
Quadrivalent influenza vaccine 466
Quarantine 120
R
Rabies 12, 679, 692, 719
higher risk for 391
immunoglobulin 392, 393
monoclonal antibodies 392
period of 390
postexposure treatment 398
tissue culture vaccines 399
transmission of 389
types of 390
vaccinated against 695
vaccination 400
prophylaxis of 394
route of 401
vaccine 389, 401, 402, 688, 730
virus 390
Randomized controlled trial 454, 565
Rapid fluorescent focus inhibition test 399
Recombinant vaccines, live 572
Refrigerator, purpose-built 106f
Renal failure, chronic 370
Resistant pathogens, surveillance of 367
Respiratory infections, acute 464
Respiratory syncytial virus 26, 188, 541, 560, 703
burden of 541
infection, risk factors of 541
vaccine 541, 543
snapshot of 544t
strategies 542
Retinoblastoma 634
Rheumatic diseases, chronic 89
Rheumatoid arthritis 650
Ribonucleic acid 302, 462, 463, 502, 558, 559, 599, 629
vaccine, modified 615
Roseola 259
Rotavirus 12, 43, 436, 588, 725
disease 434, 435
gastroenteritis 435
severe 435, 438t
infection 434
serotypes 441
vaccination 441, 442, 444
guidelines for 443
vaccine 41, 158, 434, 435, 437, 438t, 439441, 443, 724
adverse effects of 440
doses of 438
preterm babies receive 439
Rubella 12, 35, 111, 259
titer, negative 272
vaccination
certificate 684
role for 717
vaccine 278, 684
Rubini strain 275
S
Saccharomyces cerevisiae 288, 514
Safe injection practices 48
Safe vaccine storage 109
Salmonella
enterica 337
minnesota 661, 665
typhi 8, 10, 34, 120, 718
strain 336
typhimurium 607
Scar formation 180, 182
Sclerosing panencephalitis, subacute 262
Seasonal flu vaccines 474f
Seizures 259
Sentinel and population-based surveillance 65f
Sentinel surveillance 64
Serious side effects 485
Seroconversion rates 349
Serum
immunoglobulin 54
specimen testing protocol 73fc
Severe acute respiratory syndrome 121, 691
coronavirus 2 26, 35, 188, 558, 559, 632
Sexual transmission 282
Sexually transmitted diseases 447
Shigella
flexneri 184
infection 592
sonnei 592
Shigellosis 592
Sick child 58
Sickle cell disease 86, 379
Smallpox 35
Solid organ transplant 85, 576
Spirit test 400
Staphylococcus aureus 588, 665
Stem cell harvest 85
Strengthen polio 215
Streptococcus
group B 703
pneumoniae 10, 78, 363, 372
Streptomycin sulfate 48
Superfluous antigen, administration of 522
Swachh Bharat Abhiyan 335
Synthetic flu vaccines 468
Synthetic influenza vaccines 469
Synthetic peptide vaccines 584
T
T cell 607
dependent 10
antigens 14
independent immune 10
receptor 5
response, vaccine with 601
T lymphocyte 24
activation pathway 9f
defects 77
Tetanus 11
immune globulin 255
neonatal 66, 69, 71
protein 359
single-antigen 255
vaccine 45, 152
Tetanus and diphtheria 43, 46, 163, 519, 679, 730
and acellular pertussis, dose of 256
and pertussis 576
vaccine 679, 706f
Tetanus, diphtheria and acellular pertussis 519, 678, 679, 692, 730
products 254
vaccination 249
vaccine 237, 245, 256, 692
Tetanus toxoid 54, 60, 102, 105, 111113, 152, 253, 340, 723
vaccine 706f
Tetravalent dengue vaccines, live attenuated 503f
T-helper cell type 233
Therapeutic cancer vaccines 647650
Therapeutic vaccination 553, 616
Therapeutic vaccine 459, 608t, 647, 651
current status of 650
pipeline 2019 653t
status of 651
Thimerosal causes autism 278
Thrombospondin-related adhesive protein 512
vaccine 513
Tick-borne
encephalitis 432, 703
fever 640
Tissue culture vaccine 394, 397
Toll-like receptors 8
Towne vaccine 577
Towne-toledo chimera vaccines 577
Toxic shock syndrome 262
Tracheal cytotoxin 248
Trained immunity 185
Trained innate immunity 25f, 186f, 187f
Transcriptase-polymerase chain reaction, reverse 466, 526, 557, 559
Transverse myelitis 268
Tuberculosis 12, 66, 70, 162, 549, 657
disease 550
incidence, estimate of 29f
protection against 184
types of 177
vaccine 190, 551
newer 549
Tumor
antigens 647
necrosis factor 26, 188
alpha 347
Twinrix™ vaccine 308t
Typhoid 80, 333, 679, 718
conjugate 12
vaccine 335, 339, 341t, 342t, 729
fever 334f, 335, 349, 692
status of 333
immunity 347
vaccine 333, 335f, 353b, 682, 695, 718
inactivated 84
types of 335, 336t
U
United Nations International Children's Emergency Fund 146
United States Food and Drug Administration 523
Universal flu vaccine 469, 470
Universal immunization 301
Universal Immunization Program 148, 151, 158, 224, 268, 412, 436, 438, 443, 471, 716
Universal influenza vaccine 469, 470, 470b
Upper respiratory tract infection 58, 498
V
Vaccinating Healthcare professionals with flu vaccine, advantages of 714
Vaccination 75, 82, 101
contraindications to 486
dose and route of 527
epidemiology in 28
in adolescents 552
in adults 552
in infants 552
in special situations 75
instructions for 48
issues of 81
practice of 48
program 30
role of gender-neutral 451
routine 429, 679
schedule 39, 156, 398
of routine 53b, 289
Vaccine 84, 91, 131f, 170b, 595, 723, 727
administration of 44
adverse effects of 596
all-in-one 22
approval 137t
permission of 134
attenuated 8, 577
available 481
brands 91
candidates 505
carriers 115
characteristics 22
clinical development of 125
communication, reframing of 171
confidence 102
conjugate 359
contents in 527
current status of 597
delivery, methods of 536
derived polio viruses 163
development of 124, 126, 127f, 129, 129t, 571
roadmap of 124t
doses of 14, 41, 56b
and schedule of 595
efficacy 30, 452t
estimates 419t
egg-based 467
egg-derived 468
failure 290
causes of 314
formation of 596
handling of 58
hesitancy 103, 167, 169172
communication 171b
spectrum 168f
types of 167
immunity 102, 234
immunogenicity 30
role in 8
immunology of 3, 4
in pipeline 496, 535, 539
inactivated 8
induced immunity, correlates of 12t
interchangeably 455
licensing of 124
lightsensitive 111
like particles 470
live 8, 13, 15, 82t, 327, 704
attenuated 585, 591, 592
manufacturing 129
maternal 700
newer generations of 507
non-live 83t
performance of 6
poxvirus-based 432
preventable disease 17, 62, 90, 154, 161, 267
product-related reaction 94
protection of 596
quality defect-related reaction 94
reaction, type of 97
refrigerator 110
responses, effectors of 11
safe 101, 709
safety testing of 126f
schedules 158
sensitivities 112t
side effects of 313
simultaneous 519
single-antigen 296
storage 58, 107, 108
domestic refrigerator for 107f
equipment 105
subunit 560
third-generation 629
transmission-blocking 514
types of 304, 401, 437, 526, 584
combination 519
inactivated 304
use to store 108
vaccination schedule for nonlive 17
vectored 579
vial monitor 273
stage of 201
with humoral immune response 602
Vaccine-derived poliovirus
circulating 203
types of 203
Vaccine-preventable disease 67, 69t
surveillance 62
types of 64
Vaccinia ankara virus, modified 653
Vaccinia virus
herpes, and influenza 184
modified 652
Varicella 54, 80, 111, 273, 327, 329, 679, 717
breakthrough 313, 315
immunization 326
vaccination 318, 325
vaccine 312, 316, 320, 321t, 325330, 683, 717
contagiousness of 329
content of 312
efficacy of 313
Varicella zoster 63
immune globulin 327, 328
virus 312
Venous thromboembolism 453
Verbal autopsy 99
Vertical transmission 282
Vibrio cholera 491, 588
types of 492
VI-CPS vaccines, limitations of 338b
Viral infections 35
Viral pandemics 25
Virosomes 665
Virus
like particles 12, 502, 572, 584, 609, 665
vaccine, replication-defective 579
vectors 665
Vitamin A 165, 725
Vomiting 97
Vomits dose 439
Vulvar intraepithelial neoplasia 451
W
West Nile
fever 640
viruses 432
Whole virus vaccines 560
Whole-cell cholera vaccine 494
Whole-cell pertussis 50, 84
vaccine 230, 238t
Whole-limb swelling 240
Whooping cough 101
Wild polio 211
eradication of 214
transmission 213
virus 203, 215
Wild virus 577
Working cell bank 134
World Health Organization 78, 549, 594, 711
Wound
management, part of 255
suturing of 401
Y
Yellow fever 525, 525f, 526, 679, 688, 692, 703
symptoms of 526
vaccinated against 719
vaccination 530
vaccine for 525, 526, 730, 731
virus 525
Young age immunization 15, 17
Z
Zika 35
fever 611
Zika virus 525, 611, 613
infection 611, 612f, 613, 697
epidemiology of 611
live attenuated 615
structure of 612, 612f
vaccine 611, 614t
developing 616
×
Chapter Notes

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1General Vaccination
  1. Vaccine Immunology: Basics and Beyond
    Yash Paul, Vipin M Vashishtha
  2. Elementary Epidemiology in Vaccination
    Vipin M Vashishtha, Yash Paul
  3. Vaccination Schedules
    Yash Paul, Satish V Pandya
  4. Practice of Vaccination
    Yash Paul, Satish V Pandya, Atul K Agarwal
  5. Vaccine-preventable Diseases Surveillance
    Meeta Dhaval Vashi
  6. Vaccination in Special Situations
    Abhaya K Shah
  7. Adverse Events following Immunization, Vaccine Safety and Misinformation against Vaccination
    Meeta Dhaval Vashi, Vivek R Pardeshi
  8. Cold Chain and Vaccine Storage
    Digant D Shastri
  9. Control and Eradication of Infectious Diseases
    Yash Paul, Priya Marwah
  10. Development and Licensing of Vaccine
    Gautam Rambhad, Canna Jagdish Ghia
  11. National Immunization Technical Advisory Group
    Madhu Gupta, Adarsh Bansal
  12. Medicolegal and Ethical Issues in Immunization
    Satish Kamtaprasad Tiwari, Yash Paul
  13. Vaccine Schedules including National Immunization Program
    Meeta Dhaval Vashi, Vivek R Pardeshi
  14. Vaccine Hesitancy
    Chndrakant Lahariya, Dewesh Kumar2

Vaccine Immunology: Basics and BeyondCHAPTER 1

Yash Paul,
Vipin M Vashishtha
1. Are vaccination and immunization same?
Broadly speaking, both terms appear to be same and frequently used interchangeably. However, there is minor technical difference. “Vaccination” is a process of inoculating the vaccine/antigen into the body. The vaccine may or may not seroconvert to vaccine whereas the process of inducing immune response, which can be “humoral” or “cell mediated” in the vaccine is called “immunization”. Vaccines can be administered through different routes, e.g., nasal mucosa, gut mucosa, or by injection which may be given intradermal, subcutaneous, or intramuscular. This process is called “vaccination” or “active immunization”. In case immunoglobulins or antisera are administered, it is called “passive immunization”.
Thus, administration of immunoglobulins or antisera is not vaccination, although it provides immunity or protection for a short period.
2. What are “humoral” and “cell-mediated immunity”?
Vaccines confer protection against diseases by inducing both antibodies and T cells. The former is called “humoral” response and the latter “cellular” response or “cell-mediated immunity (CMI)”. Antibodies are of several different types [immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), immunoglobulin D (IgD), and immunoglobulin E (IgE)] and they differ in their structure, half-life, site of action, and mechanism of action. Humoral immunity is the principal defense mechanism against extracellular microbes and their toxins. B lymphocytes secrete antibodies that act by neutralization, complement activation, or by promoting opsonophagocytosis. CMI is the principal defense mechanism against intracellular microbes. The effectors of CMI, the T cells, are of two types. The helper T cells secrete proteins called cytokines that stimulate the proliferation and differentiation of T cells as well as other cells including B lymphocytes, macrophages, and natural killer (NK) cells. The cytotoxic T cells act by lysing infected cells.
3. What are innate and adaptive immunity?
Innate immunity comprises of the skin and mucosal barriers, phagocytes (neutrophils, monocytes, and macrophages), and the NK cells. It comes4 into play immediately on entry of the pathogen and is nonspecific. Adaptive immunity is provided by the B lymphocytes (humoral/antibody-mediated immunity) and T lymphocytes (cellular/CMI). 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 evolve and is pathogen specific (Fig. 1 and Table 1).
4. What are “B” and “T” cells? What role do they play in regard to immunology of vaccines?
Immune system is almost nonexistent at birth; maternal antibodies transferred transplacentally provide some protection during early childhood. After birth, baby comes in contact with microbes which gradually activate immune system.
zoom view
Fig. 1: Innate and adaptive immunity.Source: Abbas AK, Lichtman AH, Pillai S. Introduction to the immune system. In: Basic Immunology. 6th edition, Elsevier, 2019.
TABLE 1   Comparison of innate and adaptive immunity.
Nonspecific immunity (innate)
Specific immunity (adaptive)
Its response is antigen independent
Its response is antigen dependent
There is immediate response
There is a lag time between exposure and maximal response
It is not antigen specific
It is antigen specific
Exposure does not result in induction of memory cells
Exposure results in induction of memory cells
Some of its cellular components or their products may aid specific immunity
Some of its products may aid nonspecific immunity
5
B cells form the most important component of immune system in the body. These are produced in liver in fetal life and mature in bone marrow in humans. In other species, these cells mature in an organ called “bursa of Fabricius”, thus these lymphocytes are called B cells. On activation by an antigen contained in microorganisms and vaccines, the B cells proliferate and get converted to plasma cells, which, in turn, produce antibodies. For effective production of antibodies, B cells need help from T-helper cells. T lymphocytes are the cells that originate in the thymus, mature in the periphery, and become activated in the spleen/nodes if (1) their T-cell receptor (TCR) binds to an antigen presented by a major histocompatibility complex (MHC) molecule and (2) they receive additional costimulation signals driving them to acquire killing (mainly CD8+ T cells) or supporting (mainly CD4+ T cells) functions.
B cells have immunoglobulin surface receptor, which binds with the appropriate antigen present on the infective pathogen. The processed antigen stimulates the B cell to mature into antibody-secreting plasma cell and generates IgM. T helper 2 (Th2) cell leads to switch in the production from IgM to IgG and IgA or IgD. The B cells can directly respond to the antigen and process the antigen, but the T cells do not react with the antigen directly unless processed and presented by special cells called antigen-presenting cells (APCs).
5. What are antigen-presenting cells (APCs) and dendritic cells? What functions do they perform?
Antigen-presenting cells are the cells that capture antigens by endo- or phagocytosis, process them into small peptides, display them at their surface through MHC molecules, and provide costimulation signals that act synergistically to activate antigen-specific T cells. APCs include B cells, macrophages, and dendritic cells (DCs), although only DCs are capable of activating naïve T cells (Fig. 2).
Dendritic cells are major APC in the body in addition to the B cells and the macrophages. The major role of these cells is to identify dangers, which is done by the special receptors on the APC named Toll-like receptors (TLRs).
Vaccine antigens are taken up by immature 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 TLRs 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 [MHC-human leukocyte antigen (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.6
zoom view
Fig. 2: Schematic presentation of a dendritic cell and its activation by pathogens.Source: Siegrist CA. Vaccine immunology. Presentation delivered at 20th Advanced Course of Vaccinology, Annecy, France 2019. Available from: https://www.advac.org/images/files/members/files_presentations/2019/0900_SIEGRIST_ADVAC_2019_Immunology_slides_-_9h-11h30.pdf(IL-1: interleukin-1; MHC: major histocompatibility complex)
Antigen-specific TCRs may only bind to specific MHC molecules (e.g., HLA-A2), which differ among individuals and populations. Consequently, T-cell responses are highly variable within a population.
6. What are adjuvants? How do they affect performance of a vaccine?
Adjuvants are agents which increase the stimulation of the immune system by enhancing antigen presentation (depot formulation, delivery systems) and/or by providing costimulation signals (immunomodulators). Aluminum salts are most often used in today's vaccines. Hence, the adjuvants improve the immunogenicity of vaccines. Many new generations of adjuvants are in fact analogs of TLRs, for example, CpG-ODN is used in new generation of Japanese encephalitis vaccines.
Most nonlive vaccines require their formulation with specific adjuvants to include danger signals and trigger a sufficient activation of the innate system. These adjuvants may be divided into two categories: (1) delivery systems that prolong the antigen deposit at site of injection, recruiting more DCs into the reaction and (2) immune modulators that provide additional differentiation and activation signals to monocytes and DCs. Although progress is being made, none of the adjuvants currently in use trigger the degree of innate immune activation that is elicited by live vaccines, whose immune potency far exceeds that of nonlive vaccines.
7. What are “germinal centers” and “marginal zone”?
Germinal centers (GCs) are dynamic structures that develop in spleen/nodes in response to an antigenic stimulation and dissolve after a few weeks.7 GCs contain a monoclonal population of antigen-specific B cells that proliferate and differentiate through the support provided by follicular DCs and helper T cells. Immunoglobulin class switch recombination, affinity maturation, B-cell selection, and differentiation into plasma cells or memory B cells essentially occur in GCs.
“Marginal zone” is the area between the red pulp and the white pulp of the spleen. Its major role is to trap particulate antigens from the circulation and present it to lymphocytes.
8. What do the terms “epitope” and “paratope” mean?
An “epitope” refers to the specific target against which an individual antibody binds. When an antibody binds to a protein, it is not binding to the entire full-length protein. Instead, it is binding to a segment of that protein known as an “epitope”. Hence, an epitope is a specific part of the antigen that elicits an immune response.
Binding between the antibody and the epitope occurs at the antigen-binding site, which is called a “paratope” and is located at the tip of the variable region on the antibody. This paratope is only capable of binding with one unique epitope.
9. What is the difference between “antibody affinity” and “avidity”?
The antibody affinity refers to the tendency of an antibody to bind to a specific epitope at the surface of an antigen, i.e., to the strength of the interaction. The avidity is the sum of the epitope-specific affinities for a given antigen. It directly relates its function.
10. What do the terms “CD4+ T cells” and “CD8+ T cells” stand for? What are the functions of these lymphocytes?
CD4+ T cells are those T lymphocytes that express the cluster of differentiation 4 (CD4) glycoprotein at their surface. CD4 is a glycoprotein expressed on the surface of T-helper cells, regulatory T cells, monocytes, macrophages, and DCs. It was discovered in the late 1970s and was originally known as Leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene. CD4 is a coreceptor that assists the TCR to activate its T cell following an interaction with an APC. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as the tyrosine kinase Lck, which is essential for activating many molecules involved in the signaling cascade of an activated T cell. CD4 interacts directly with MHC class II molecules on the surface of the APC using its extracellular domain.
T cells expressing CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC class II and not by MHC class I (they are MHC class II-restricted). The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to interact with the Lck molecule described above.8
CD8+ cells are those T lymphocytes that express the CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of nearly every cell of the body. Through IL-10, adenosine, and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis. CD8+ cells are cytotoxic T lymphocytes (CTLs) and destroy virally infected cells and tumor cells and are also implicated in transplant rejection (Fig. 3).
CD8+ T cells do not prevent, but reduce, control, and clear intracellular pathogens by:
Directly killing infected cells (release of perforin, granzyme, etc.)
Indirectly killing infected cells through antimicrobial cytokine release.
CD4+ T cells do not prevent but participate to the reduction, control, and clearance of extra- and intracellular pathogens by:
Producing interferon-γ (IFN-γ), tumor necrosis factor-α/-β (TNF-α/-β), interleukin-2 (IL-2) and IL-3, and supporting activation and differentiation of B cells, CD8+ T cells, and macrophages [T helper 1 (Th1) cells].
Producing IL-4, IL-5, IL-13, IL-6 and IL-10, and supporting B-cell activation and differentiation (Th2 cells).
11. What are toll-like receptors (TLRs) and their role in vaccine immunogenicity?
Toll-like receptors are a family of 10 receptors (TLR1 to TLR10) present at the surface of many immune cells, which recognize pathogens through conserved microbial patterns and activate innate immunity when detecting danger. TLRs are a key driver of innate immune response. They can recognize an invading pathogen through structurally conserved molecules of that particular pathogen collectively referred to as pathogen-associated molecular patterns (PAMPs) that are different from the host molecules. They later activate a cascade of immune responses that clear the infection. Many TLRs are now employed as adjuvants in novel vaccine products.
12. What are the differences between live attenuated and inactivated vaccines?
Live vaccines are attenuated (modified) live organisms, which have immunogenicity, i.e., can generate antibodies, but have lost pathogenicity, i.e., capability to cause disease. Live vaccines can be viral as well as bacterial. The live vaccine particles (viruses or bacteria) replicate or multiply in the body after administration and stimulate the immune system. The older concept that single dose of live vaccines induces lifelong immunity perhaps does not hold true, we need many doses of oral polio vaccine (OPV) and booster doses are required for live vaccines such as measles vaccine, varicella, rubella, and live oral typhoid vaccines. Inactivated vaccines may consist of whole-inactivated organisms such as whole-cell pertussis, typhoid, rabies; inactivated polio vaccine, modified exotoxins called “toxoids” such as diphtheria toxoid or tetanus toxoid; subunits such as polysaccharide antigens of Salmonella typhi, Haemophilus influenzae type b (Hib), and surface proteins of hepatitis B virus.9 Conjugation of the polysaccharide with a protein carrier significantly improves the immune response.
zoom view
Fig. 3: T lymphocyte activation pathway.
Live viral vaccines do efficiently trigger the activation of the innate immune system, presumably through pathogen-associated signals [such as viral ribonucleic acid (RNA)] allowing their recognition by pattern recognition receptors (PRRs)—TLRs. Following injection, viral particles rapidly disseminate throughout the vascular network and reach their10 target tissues. This pattern is very similar to that occurring after a natural infection, including the initial mucosal replication stage for vaccines administered through the nasal/oral routes. Following the administration of a live viral vaccine and its dissemination, DCs are activated at multiple sites, migrate toward the corresponding draining lymph nodes, and launch multiple foci of T- and B-cell activation. This provides a first explanation to the generally higher immunogenicity of live versus nonlive vaccines.
The strongest antibody responses are generally elicited by live vaccines that better activate innate reactions and thus better support the induction of adaptive immune effectors. Nonlive vaccines frequently require formulation in adjuvants, of which aluminum salts are particularly potent enhancers of antibody responses and thus included in a majority of currently available vaccines. This is likely to reflect their formation of a deposit from which antigen is slowly deabsorbed and released, extending the duration of B- and T-cell activation, as well as the preferential induction of IL-4 by aluminum-exposed macrophages.
Very few nonlive vaccines induce high and sustained antibody responses after a single vaccine dose, even in healthy young adults. Primary immunization schedules, therefore, usually include at least two vaccine doses, optimally repeated at a minimal interval of 3–4 weeks to generate successive waves of B cell and GC responses. These priming doses may occasionally be combined into a single “double” dose, such as for hepatitis A or B immunization. In any case, however, vaccine antibodies elicited by primary immunization with nonlive vaccines eventually wane.
13. What is the difference between T cell-dependent and T cell-independent immune response?
Certain antigens, primarily proteins, induce both B-cell and T-cell stimulation leading to what is called T cell-dependent immune response. Infants of 6 weeks of age onward are capable of T cell-dependent response. This type of response usually results in higher titers of IgG type and long lasting. It also shows booster effects with repeated exposures.
On the other hand, T cell-independent response being only B-cell mediated is not possible below 2 years of age. It is predominantly IgM type with low titers. The response is short lasting and repeated doses of vaccine do not lead to boosting effect. IgA is not produced and hence there is no local mucosal protection with this type of antigens, while in case of T cell-dependent response IgA antibodies are also produced which help in providing mucosal protection and eradication of the carrier state. Few examples of T cell-independent vaccines include bacterial polysaccharide (PS) vaccines such as Streptococcus pneumoniae (S. pneumoniae), Neisseria meningitidis, Haemophilus influenzae (H. influenzae), and Salmonella typhi.
14. What are conjugate vaccines?
As already mentioned in answer to above question, regarding the difference between T cell-dependent and T cell-independent immune response, in11 T cell-independent immune response, being B-cell mediated, younger children do not respond to such vaccines. A T cell-independent antigen like PS can be made into T cell dependent by the technique of conjugation. Such conjugated vaccines can be administered to children <2 years of age also. This technique is used to produce conjugated Vi typhoid, Hib, and pneumococcal and meningococcal vaccines.
15. How do vaccines elicit their responses? Which are the main effectors of vaccine responses?
The nature of the vaccine exerts a direct influence on the type of immune effectors that are predominantly elicited and mediate protective efficacy (Table 2). Capsular PSs elicit B-cell responses in what is classically reported as a T-independent manner, although increasing evidence supports a role for CD4+ T cells in such responses. The conjugation of bacterial PS to a protein carrier (e.g., glycoconjugate vaccines) provides foreign peptide antigens that are presented to the immune system and thus recruits antigen-specific CD4+ T helper cells in what is referred to as T-dependent antibody responses. A hallmark of T-dependent responses, which are also elicited by toxoid, protein, inactivated, or live attenuated viral vaccines, is to induce both higher-affinity antibodies and immune memory. In addition, live attenuated vaccines usually generate CD8+ cytotoxic T cells. The use of live vaccines/vectors or of specific novel delivery systems [e.g., deoxyribonucleic acid (DNA) vaccines] appears necessary for the induction of strong CD8+ T-cell responses. Most current vaccines mediate their protective efficacy through the induction of vaccine antibodies, whereas Bacillus Calmette-Guérin (BCG)-induced T cells produce cytokines that contribute to macrophage activation and control of Mycobacterium tuberculosis. The induction of antigen-specific immune effectors (and/or of immune memory cells) by an immunization process does imply that these antibodies, cells, or cytokines represent surrogates or even correlates of vaccine efficacy. This requires the formal demonstration that vaccine-mediated protection is dependent—in a vaccinated individual—upon the presence of a given marker such as an antibody titer or a number of antigen-specific cells above a given threshold. Antigen-specific antibodies have been formally demonstrated as conferring vaccine-induced protection against many diseases.
Passive protection may result from the physiological transfer of maternal antibodies (e.g., tetanus) or the passive administration of immunoglobulins or vaccine-induced hyperimmune serum (e.g., measles, hepatitis, varicella, etc.). Such antibodies may neutralize toxins in the periphery at their site of production in an infected wound (tetanus) or throat (diphtheria). They may reduce binding or adhesion to susceptible cells/receptors and thus prevent viral replication (e.g., polio) or bacterial colonization (glycoconjugate vaccines against encapsulated bacteria) if present at sufficiently high titers on mucosal surfaces. The neutralization of pathogens at mucosal surfaces is mainly achieved by the transudation of vaccine-induced serum IgG antibodies.12
TABLE 2   Correlates of vaccine-induced immunity.
Vaccines
Vaccine type
Serum IgG
Mucosal IgG
Mucosal IgA
EPI vaccines
Diphtheria toxoid
Toxoid
++
(+)
Pertussis, whole cell
Killed
++
Pertussis, acellular
Protein
++
Tetanus toxoid
Toxoid
++
Measles
Live attenuated
++
Polio Sabin
Live attenuated
++
++
++
Polio Salk
Killed
++
+
Tuberculosis (BCG)
Live mycobacterial
Non-EPI vaccines
Hepatitis A
Killed
++
(+)
Hepatitis B (HbsAg)
Protein
++
Hib PS
PS
++
(+)
Hib glycoconjugates
PS protein
++
++
Influenza
Killed subunit
++
(+)
Influenza intranasal
Live attenuated
++
+
+
Meningococcal PS
PS
++
(+)
Meningococcal conjugate
PS protein
++
++
Mumps
Live attenuated
++
Pneumococcal PS
PS
++
(+)
Pneumoccoccal conjugates
PS protein
++
++
Rabies
Killed
++
Rotavirus
VLPs
(+)
(+)
++
Rubella
Live attenuated
++
Typhoid PS
PS
+
(+)
Varicella
Live attenuated
++
Yellow fever
Live attenuated
++
Typhoid conjugate
(BCG: Bacillus Calmette-Guèrin; EPI: Expanded Program on Immunization; Hib: Haemophilus influenzae type b; IgA: immunogloblulin A; IgG: immunoglobulin G; PS: polysaccharide; VLPs: virus-like particles) Source: With permission from Siegrist CA. Vaccine immunology. In: Plotkin SA, Orenstein W, Offit P (Eds). Vaccines, 5th edition. Philadelphia: Saunders Elsevier; 2008. pp. 17-36.
It requires serum IgG antibody concentrations to be of sufficient affinity and abundance to result into “protective” antibody titers in saliva or mucosal secretions. As a rule, such responses are not elicited by PS bacterial vaccines but achieved by glycoconjugate vaccines, which therefore prevent nasopharyngeal colonization in addition to invasive diseases.13
Under most circumstances, immunization does not elicit sufficiently high and sustained antibody titers on mucosal surfaces to prevent local infection. It is only after having infected mucosal surfaces that pathogens encounter vaccine-induced IgG serum antibodies that neutralize viruses, opsonize bacteria, activate the complement cascade, and limit their multiplication and spread, preventing tissue damage and thus clinical disease. That vaccines fail to induce sterilizing immunity is, thus, not an obstacle to successful disease control, although it represents a significant challenge for the development of specific vaccines such as against human immunodeficiency virus-1 (HIV-1). Current vaccines mostly mediate protection through the induction of highly specific IgG serum antibodies. Under certain circumstances, however, passive antibody-mediated immunity is inefficient (tuberculosis).
16. What are the clinical scenarios where evidences of T-cells protection are available?
Bacillus Calmette-Guérin is the only currently used human vaccine for which there is conclusive evidence that T cells are the main effectors. However, there is indirect evidence that vaccine-induced T cells contribute to the protection conferred by other vaccines. CD4+ T cells seem to support the persistence of protection against clinical pertussis in children primed in infancy, after vaccine-induced antibodies have waned. Another example is that of measles immunization in 6-month-old infants. 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. These children remain susceptible to measles infection, but are protected against severe disease and death, presumably 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. The understanding of vaccine immunology, thus, requires appraising how B- and T-cell responses are elicited, supported, maintained, and/or reactivated by vaccine antigens.
17. What happens once a vaccine is administered to a vaccinee?
Following injection, the vaccine antigens attract local and systemic DCs, monocytes, and neutrophils. These activated cells change their surface receptors and migrate along lymphatic vessels to the draining lymph nodes where the activation of T and B lymphocytes takes place. In case of killed vaccines, there is only local and unilateral lymph node activation. Conversely, for live vaccines, there is multifocal lymph node vaccination due to microbial replication and dissemination. Consequently, the immunogenicity of killed vaccines is lower than the live vaccines; killed vaccines require adjuvants which improve the immune response by producing local inflammation and recruiting DCs/monocytes to the injection site. Secondly, the site of administration of killed vaccines is of importance; the intramuscular route which is well-vascularized and has a large number of patrolling DCs is preferred over the subcutaneous route. The site of administration is usually14 of little significance for live vaccines. Finally, due to focal lymph node activation, multiple killed vaccines may be administered at different sites with little immunologic interference. Immunologic interference may occur with multiple live vaccines, unless they are given on the same day, at least 4 weeks apart or at different sites.
18. What are the immune responses of T cell-independent antigens (i.e., polysaccharide vaccines) at the cellular level?
On being released from the injection site, these antigens usually nonprotein, PSs in nature, reach the marginal zone of the spleen/nodes, and bind to the specific immunoglobulin surface receptors of B cells. In the absence of antigen-specific T cell help, B cells are activated, proliferated, and differentiated in plasma cells without undergoing affinity maturation in GCs. 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 <2 years due to immaturity of the marginal zones. As PS antigens do not induce GCs, bonafide memory B cells are not elicited. Consequently, subsequent reexposure to the same PS results in a repeat primary response that follows the same kinetics in previously vaccinated as in naïve individuals.
19. What is hyporesponsiveness of repeated doses of a vaccine referring to?
Revaccination with certain bacterial PSs, of which group C meningococcus is a prototype—may even induce lower antibody responses than the first immunization, a phenomenon referred to as hyporesponsiveness whose molecular and cellular bases are not yet fully understood.
20. What are the immune responses of T cell-dependent antigens at the cellular level?
T cell-dependent antigens include protein antigens which may consist of either pure proteins [hepatitis B, hepatitis A, human papillomavirus (HPV), and toxoids] or conjugated protein carrier with PS antigens (Hib, meningococcal, and pneumococcal). The initial response to these antigens is similar to PS antigens. However, the antigen-specific helper T cells that have been activated by antigen-bearing DCs trigger some antigen-specific B cells to migrate toward follicular dendritic cells (FDCs), initiating the GC reaction. In GCs, B cells receive additional signals from follicular T cells and undergo massive clonal proliferation, switch from IgM toward IgG/IgA, undergo affinity maturation, and differentiate into plasma cells secreting large amounts of antigen-specific antibodies. Most of the plasma cells die at the end of GC reaction and thus decline in antibody levels is noted 4–8 weeks after vaccination. However, a few plasma cells exit nodes/spleen and migrate to survival niches mostly located in the bone marrow, where15 they survive through signals provided by supporting stromal cells and this results in prolonged persistence of antibodies in the serum.
21. What are “memory B cells”?
Memory B cells are those B lymphocytes that generate in response to T-dependent antigens, during the GC reaction, in parallel to plasma cells. They persist there as resting cells until reexposed 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.
22. What are the characteristics of immune response to live vaccines?
The live vaccines induce an immune response similar to that seen with protein vaccines. However, the uptake of live vaccines is not 100% with the first dose. Hence, more than one dose is recommended with most 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 the vaccine is, therefore, mostly for primary vaccine failures (no uptake of vaccine) and not for secondary vaccine failures (decline in antibodies overtime).
23. What determines the intensity and duration of immune responses?
The nature of antigen is the primary determinant; broadly speaking, live vaccines are superior (exception BCG, OPV) to protein antigens, which, in turn, are superior to PS vaccines. Adjuvants improve immune responses to inactivated vaccines. Immune response is usually better with higher antigen dose (e.g., hepatitis B). The immune response improves with increasing number of doses and increased spacing between doses. Technically, 0, 1, and 6 months are the best immunization schedule; the first two doses are for induction and the long gap between the second and third doses allows for affinity maturation of B cells and clonal selection of the fittest B cells for booster and memory response. Extremes of age and disease conditions lower immune response.
24. What are the limitations of young age immunization?
Young age limits antibody responses to most vaccine antigens since maternal antibodies inhibit antibodies responses, but not T-cell response and due to limitation of B-cell response.
Immunoglobulin G 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,16 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. However, even during early life, induction of memory B cells is not limited.
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 glycol-conjugate vaccines, even the most potent glycoconjugate vaccines elicit markedly lower primary IgG responses in young infants.
Although maternal antibodies interfere with the induction of infant antibody responses, they may allow a certain degree of priming, i.e., 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. Importantly, however, antibodies of maternal origin do not exert their inhibitory influence on infant T-cell responses, which remain largely unaffected or even enhanced.
The extent and duration of the inhibitory influence of maternal antibodies increase with gestational age, e.g., with the amount of transferred immunoglobulins and declines with postnatal age, as maternal antibodies wane.
25. Maternal antibodies interfere with neonatal immune responses, why hepatitis B, Bacillus Calmette-Guérin (BCG), and oral polio vaccine (OPV) are recommended at birth?
The first dose of hepatitis B, which is administered at birth, acts as “priming dose” while subsequent doses provide an immune response even in presence of maternal antibodies. As mentioned above, maternal antibodies do not interfere with induction of memory B cells, certain degree of priming is allowed. However, hepatitis B vaccine induces lower primary IFN-γ responses and higher secondary Th2 responses in early life than adults. Similarly, antibodies of maternal origin do not exert their inhibitory influence on infant T-cell responses. Since, BCG mainly works by inducing T-cell immune response hence it can be given in the presence of maternal antibodies which may even enhance T-cell responses. OPV is given at birth, since there are no maternal IgA in the gut to neutralize the virus. However, IFN-γ responses to OPV are significantly lower in infants than in adults.
26. How maternal antibodies can sometimes enhance T-cell responses of Bacillus Calmette-Guérin (BCG) vaccine administered at birth?
After administration of BCG, the maternal antibodies form immune complexes with the vaccine antigens. These immune complexes are taken17 up by more and more number of macrophages and DCs, which, in turn, are dissociated into their acidic phagolysosome compartment and are processed into small peptides. These peptides are displayed at the surface of APCs, thus available for binding by more number of CD4+ and CD8+ T cells.
27. Considering the numerous limitations of young age immunization, why still vaccines are administered at much younger age in developing countries than in developed world?
This can be explained on the basis of disease epidemiology of vaccine-preventable diseases (VPDs). Since, majority of childhood infectious diseases cause early morbidity and mortality in poor, developing countries, hence the need to protect the children before wild organisms infect them. This is the reason why early, accelerated schedules are practiced in developing countries. According to the World Health Organization (WHO) estimates, 2.5–3 million infants are born healthy but succumb to acute infections between the age of 1 and 12 months. These early deaths are caused by a limited number of pathogens, such that the availability of a few additional vaccines that would be immunogenic soon after birth would make a huge difference on this disease burden.
28. How limitations of young age immunization can be taken care of?
They can be countered by increasing the number of 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.
29. Which is the best vaccination schedule for nonlive vaccines acting on the principal of “prime-boost” mechanism?
Traditionally, 0–1–6 months schedule is considered as a most immunogenic schedule than 6–10–14 weeks or 2–3–5 months schedule for nonlive T cell-dependent vaccines like hepatitis B vaccine. This is mainly due to proper spacing of the vaccine doses and adequate time interval between first few doses which act by inducing 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 (Fig. 4).
Immunization schedules commencing at 2 months and having 2 months spacing between the doses are technically superior to that at 6, 10, and 14 weeks. However, for operational reasons and for early completion of immunization and attainment of protection, the 6, 10, 14 and weeks schedule is chosen in developing countries.18
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Fig. 4: Schematic presentation of various components of 0, 1, and 6 months immunization schedule at cellular level.(IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M)Source: Siegrist CA. Vaccine immunology. Presentation delivered at 20th Advanced Course of Vaccinology, Annecy, France 2019. Available from: https://www.advac.org/images/files/members/files_presentations/2019/0900_SIEGRIST_ADVAC_2019_Immunology_slides_-_9h-11h30.pdf
Accelerated infant vaccine schedules in which three vaccine doses are given at a 1-month interval (2, 3, 4 months or 3, 4, 5 months) result into lower responses than schedules in which more time elapses between doses (2, 4, and 6 months) or between the priming and boosting dose (3, 5, and 12 months). However, the magnitude of infant antibody responses to multiple dose schedules reflects both the time interval between doses, with longer intervals eliciting stronger responses and the age at which the last vaccine dose is administered.
30. What is a primary and secondary immune response?
When an antigen is introduced for the first time, the immune system responds primarily after a lag phase of up to 10 days. This is called the primary response. Subsequently, upon reintroduction of the same antigen, there is no lag phase and the immune system responds by producing antibodies immediately and this is called the secondary response. However, there are some differences in both these responses—primary response is short-lived, has a lag phase, predominantly IgM type, and antibodies titers are low, whereas secondary response is almost immediate without a lag phase, titers persist for a long time, predominantly of IgG type, and antibodies titers are very high.19
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Fig. 5: Correlation of antibody titers to various phases of the vaccine response. The initial antigen exposure elicits an extrafollicular response (1) that results in the rapid appearance of low immunoglobulin G (IgG) antibody titers. As B cells proliferate in germinal centers and differentiate into plasma cells, IgG antibody titers increase up to a peak value (2) usually reached 4 weeks after immunization. The short lifespan of these plasma cells results in a rapid decline of antibody titers (3) which eventually return to baseline levels (4). In secondary immune responses, booster exposure to antigen reactivates immune memory and results in a rapid (<7 days) increase (5) of IgG antibody titer. Short-lived plasma cells maintain antibody (6) during a few weeks—after which serum antibody titers decline initially with the same rapid kinetics as following primary (7) 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 (8) kinetics.Note: This generic pattern may not apply to live vaccines triggering long-term IgG antibodies for extended periods of time.Source: With permission from Siegrist CA. Vaccine immunology. In: Plotkin SA, Orenstein W, Offit P (Eds). Vaccines, 5th edition. Philadelphia: Saunders Elsevier; 2008. pp. 17-36.
Figure 5 describes the background developments at the cellular level and interactions of B cells, memory B cells, and T cells at the follicular level in a lymph node. The secondary response is mainly due to booster response and is seen with vaccines that work on a “prime-boost” mechanism inducing T cells such as conjugate vaccines. On the other hand, nonconjugate, polysaccharide vaccines mainly induce primary response and the repeat dose produces another wave of primary response and not acts as a booster since they do not induce T cells.
31. What are the hallmarks of “memory B cell” responses?
These cells are only generated during T cell-dependent responses inducing GCs responses. These cells are resting cells that do not produce antibodies. Memory B cells undergo affinity maturation during several (4–6) months. A minimal interval of 4–6 months is required for optimal affinity maturation of memory B cells. Memory B cells rapidly (days) differentiate into antibody-secreting plasma cells upon reexposure to antigen. Memory B cells20 differentiate into PCs that produce high(er) affinity antibodies than primary plasma cells. As plasma cells and memory responses are generated in parallel in GCs, higher postprimary antibody titers reflect stronger GC reactions and generally predict higher secondary responses. During induction, a lower antigen dose at priming results in inducing B cells differentiation away from PCs, toward memory B cells. This phenomenon can be exploited by using small amount of expensive conjugate vaccines such as pneumococcal conjugate vaccine (PCV) followed by use of less expensive pneumococcal polysaccharide vaccine (PPV) as booster. Exposure to exogenous antigens may reactivate or favor the persistence of memory B cells.
32. What are the implications of “immune memory” for immunization programs?
Immune memory is seen with live vaccines/protein antigens due to generation of memory B cells which are activated on repeat vaccination/natural exposure. Immune memory allows one to complete an interrupted vaccine schedule without restarting the schedule. Hence, immunization schedule should never be started all over again regardless of duration of interruption. Regular boosters are not required to maintain immune memory during low risk periods (travelers). Certain immunization schedules may not need boosters, if exposure provides regular natural boosters. Activation of immune memory and generation of protective antibodies usually take 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 and hepatitis B do not need regular boosters as the long incubation period of the disease allows for activation of immune memory cells. This is to be noted that memory B cells do not produce antibodies unless reexposed to antigen which drives their differentiation into antibody-producing plasma cells.
33. Why is number of doses for each vaccine different?
Live attenuated vaccines replicate (in case of viruses) or multiply (in case of bacteria) in the body thus, the number of vaccine particles increases many folds which are capable of generating antibodies in large quantity to reach seroprotective levels. Due to some reasons, not fully understood, multiple doses of OPV are needed. On the other hand, inactivated vaccines do not multiply in the body and quantity of vaccine (antigens) required to provide full protection is large; fever and local reactions such as swelling, tenderness, and pain may be very severe, if the required quantity of vaccine is administered at a time, so the quantity of vaccine is generally divided in two or more doses. Diphtheria, pertussis, and tetanus (DPT) is divided in three doses while rabies vaccine is divided in four or five doses.
34. Why do we need booster (booster doses)?
The body starts antibody generation after administration of vaccines, which reach a peak after a period of time which is different for different vaccines.21 As already stated, multiple doses of some vaccines have to be administered to attain optimal level of immunity. Over a period of time, which also varies for different vaccines, antibody level declines and revaccination or booster dose(s) is/are required to raise the antibody levels above the required protective levels.
In most cases, subclinical infection acts as a booster dose. As the percentage of vaccinated and immune population increases, circulation of the causative organisms declines in the community. This decline in circulation of organisms lessens the chances of nonimmune individuals in coming in contact with organisms (which is a beneficial for nonimmune people), but those immune following vaccination may be deprived of the benefit of repeated subclinical exposure leading to boosting effect. This is the reason that booster dose for varicella vaccine has been introduced in those countries where vaccine coverage is very high.
35. Why we need to give only one dose of a particular vaccine while multiple doses are needed for another vaccine?
In general, live vaccines generate antibodies to protective levels after administration while antigens need multiple doses because the quantity required to generate antibodies to protective levels is very large, so multiple doses are required.
It has been observed that natural infection with viral diseases provides very long or lifelong protection while infections by bacteria do not provide any long-lasting protection. Typhoid disease, skin infections, and other infections caused by bacteria can recur again and again while second attack of measles or chickenpox occurs rarely, if at all. Similarly, antibodies produced by antiviral vaccines persist for much longer period as compared to antibodies produced by antibacterial vaccines.
36. Do all inactivated vaccines need booster doses? How long after the primary doses are boosters advised? Why?
  • No, certain vaccines such as hepatitis A, hepatitis B, HPV, etc., do not require frequent boosters.
  • To believe that a single dose or a primary course of vaccination provides a lifelong immunity is a utopian thought. It does not exist because it could not exist. Not only inactivated, but even most live vaccines do need extra doses! Even for some of the highly efficacious live vaccines like measles, we need extra doses.
  • The need and timing of boosters further depend on three factors: (1) related to the agent (microbe), (2) host, and (3) vaccine characteristics.
    1. Agent (microbe): If the incubation period of a disease is short than the time required for reactivation of memory B cells, plasma cells secrete antibodies. Boosters needed as incubation period is short in diseases such as diphtheria, tetanus, Hib, and pneumococcus, but not needed as incubation period is long such as in hepatitis B, hepatitis A, HPV, etc. It is generally considered that protection by22 toxoid-based vaccines requires the presence of antitoxin antibodies at time of toxin exposure. This is supported by the observation that despite the occurrence of many adult cases of diphtheria during a large outbreak in the former Soviet Union, a single vaccine dose raised strong antibody responses to this relatively poor immunogen. This confirmed that most patients had been immunized in childhood and had lost vaccine antibodies over time, but had persistent immune memory. This immune memory was however not sufficient to protect against diphtheria, a disease characterized by a short incubation period (1–5 days).
    2. Vaccine characteristics: It depends on the quality of immunogen and the vaccine-elicited immune responses. Take the case of another vaccine like flu vaccines. The immunity persists only for few months. Pertussis vaccines: you need frequent boosters. Japanese encephalitis (JE) vaccines: Old mouse brain: frequent boosters but new generation: only infrequently needed. We are now developing more new technology to have more durable immunity like use of nanoparticles, better adjuvants such as TLRs agonists, new delivery techniques, etc.
    3. Host: For example, in immunocompromised host with congenital/acquired immunodeficiency states (such as HIV, asplenia, complement deficiency, chronic illnesses, immunosuppressive drugs, malignancy, etc.), one needs frequent boosters to maintain a baseline antibodies level to accord protections.
37. Why cannot we have an “all-in-one vaccine”?
There are very strong scientific and logistic reasons against “all-in-one vaccine”. Scientific reasons are: (i) different ideal ages for different vaccines, e.g., OPV, BCG, and hepatitis B vaccines can be administered soon after birth, other vaccines cannot be administered at this age; (ii) different routes of administration, e.g., some are administered orally, others are administered parentally, some are administered intradermally (BCG), some are administered subcutaneously [measles, measles, mumps, and rubella (MMR), and varicella vaccines], and other vaccines are administered intramuscularly. Logistic reasons are: (i) some vaccines need to be administered as a single dose (BCG and varicella vaccines), some vaccines need two doses (such as measles, MMR, hepatitis A, and rotavirus vaccine), some vaccines need three doses (hepatitis B and HPV vaccines) while other vaccines have to be administered at different intervals and (ii) quantity of such an “all-in-one vaccine” would be too large. Certainly, the idea appears to be very attractive, but does not appear feasible in foreseeable future.
38. Few vaccines such as diphtheria, tetanus, and pertussis (DTP) vaccine causes higher incidence of fever, pain, tenderness, and other local reactions. Should antipyretics such as paracetamol, ibuprofen, etc., be prescribed prophylactically routinely?23
Prophylactic antipyretic administration decreases the postvaccination adverse reactions. Recent study finds that they may also decrease the antibody responses to several vaccine antigens.
Though prophylactic antipyretic administration leads to relief of the local and systemic symptoms after primary vaccinations, there is a reduction in antibody responses to some vaccine antigens without any effect on the nasopharyngeal carriage rates of S. pneumoniae and H. influenzae serotypes. Immunologically, this can be explained by reductions in “danger signals” due to anti-inflammatory effects of these compounds that “blunt” the antibodies production (Fig. 6). The development of fever or increase in the temperature postvaccination is due to the release of endogenous cytokines (IL-1 and TNF-α).
However, since the antibody response [geometric mean concentration (GMC)] was not reduced below seroprotection level, it is unlikely that prophylactic paracetamol (PCM) would have any detrimental effect for individual child concerned. Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic administration of PCM is given. The timing of administration of antipyretics should be discussed with the parents after explaining the benefits and risks.
39. Immune memory is the function of adaptive immune system. Do innate immune systems also display memory responses?
Unlike the “adaptive” immunity, the “innate” immune system is supposed to have no memory responses. Recently, the phenomenon of vertebrate innate memory has experienced a renewed interest. This phenomenon is best exemplified by in vivo vaccination with the BCG that could induce a more effective host immune response to subsequent challenges, with a concomitant increase in resistance to unrelated infections. BCG, which can remain alive in the human skin for up to several months, triggers not only Mycobacterium-specific memory B and T cells but also stimulates the cells of the innate system (monocytes, neutrophils, macrophages, natural killer, DCs, etc.) for a prolonged period. The process by which BCG imparts immune memory to the innate system is known as “trained innate immunity”, which, in turn, is elicited by a phenomenon known as “epigenetic effect”.
“Epigenetic effect” is produced by the modification of gene expression rather than alteration of the genetic code or nucleotide sequencing. This effect is brought about by two main mechanisms, DNA methylation and histone modifications that alter innate immunity. BCG does epigenetic reprogramming in the training of innate cells, particularly monocytes. Upon pathogen X recognition by a receptor, “naïve” monocytes undergo epigenetic reprogramming and a metabolic shift and convert into “trained” monocytes, primed to respond more vigorously to nonspecific (pathogens X, Y, and Z) secondary stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Later on, these “trained” monocytes have a significantly higher production of several proinflammatory cytokines [such as IFN-γ, TNF-α, interleukins (IL-1β, IL-6, etc.] upon heterologous challenges, particularly T helper cell type 1 polarizing and typically monocyte-derived proinflammatory cytokines that help in rapid clearance of infection (Fig. 7).24
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Fig. 6: “Danger signals”/adjuvants activate dendritic cells (DCs) directly or indirectly.(iNKT: invariant natural killer T; iTCR: invariant T-cell receptor; MPL: monophosphoryl lipid A; MSU: monosodium urate; PLG: poly-α-L-glutamine; TLRs: Toll-like receptors)Source: De Gregorio E, D’Oro U, Wack A. Immunology of TLR-independent vaccine adjuvants. Curr Opin Immunol. 2009;21(3):339-45.
These modified, activated, and “trained” cells can be stimulated by various nonrelated infectious (viruses, bacteria, fungi and their components, parasites) or noninfectious agents such as nanoparticles which lead to potent immune memory responses. This response explains the BCGs nonspecific protection against sepsis, pneumonia, and other pathogens. Both epigenetic changes and increased nonspecific immune responses could be detected up to 1 year after BCG vaccination.
40. What are the differentiating features of adaptive and innate memory responses?
Innate immune memory differs from adaptive memory for many aspects, including the lack of gene rearrangements, the involvement of epigenetic reprogramming, the type of cells involved (innate cells vs. T and B lymphocytes), and the receptors engaged in pathogen/antigen recognition (selective PRRs vs. antigen-specific T-cell and B-cell receptors). In general, innate memory is considered as a nonspecific short-lived phenomenon, as opposed to adaptive memory that is long-lived and highly specific.25
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Fig. 7: “Trained innate immunity”—epigenetic reprogramming of monocytes. Upon pathogen X recognition by a receptor, naïve monocytes undergo epigenetic reprogramming and a metabolic shift and become primed to respond more robustly to nonspecific (pathogens X, Y, and Z) secondary stimulation.(DNA: deoxyribonucleic acid; IFN-γ: interferon-γ; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α)Source: Vashishtha VM. Are BCG-induced non-specific effects adequate to provide protection against COVID-19? Hum Vaccin Immunother. 2020;7:1-4.
41. Can trained immunity may offer some protection against ongoing coronavirus disease 2019 (COVID-19) pandemic or other future viral pandemics?
Theoretically, the nonspecific, innate immunity shall provide some temporary protection against an unrelated viral pathogen through trained immunity. BCG is the vaccine to be tried for this purpose. It may have some utility owing to induction of strong, nonspecific, and innate immune responses in the vaccinated subjects. One should not expect significant inhibitory responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, but even “stop gap” protection and some attenuation of the disease may be expected against coronavirus disease 2019 (COVID-19). An extra dose of BCG to the healthcare workers and elderly people with comorbid conditions would be worth trying till a specific vaccine is developed (Figs. 8A to C).
Bacillus Calmette-Guérin is generally safe and well-tolerated. However, it is contraindicated in immunocompromised individuals, so one needs to be extra careful while administering BCG to these individuals. Whether the heterologous immunity would be adequate to neutralize the virus at its first portal of entry? Would the quantum of innate immune responses elicited in adults and elderly be at par with those produced in young children? Would BCG revaccination be safe in Mycobacterium tuberculosis-infected and uninfected populations? Would it be safe to administer a live vaccine to elderly with comorbidities? Which BCG strain would elicit the greatest nonspecific immunity? These are some of the queries that need urgent resolution.26
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Figs. 8A to C: Trained immunity antiviral host defense and its role in a new viral pandemic. (A) BCG vaccination has been shown to protect against multiple viral pathogens; (B) Trained immunity leading to enhanced innate immune responses to different pathogens after a vaccination is mediated by metabolic and epigenetic rewiring in innate immune cells, which lead to increased gene transcription and improved host defense; and (C). Trained immunity as a tool for enhancing population immunity during a pandemic ahead of the availability of a specific vaccine.(BCG: Bacillus Calmette-Guérin; HSV: herpes simplex virus; IL-6: interleukin-6; RSV: respiratory syncytial virus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNF: tumor necrosis factor)Source: O’Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20(6):335-7.
27
As discussed above, the main argument against the ecological studies linking universal BCG use with protection against COVID-19 is the waning of BCG-induced immunity. But even if heterologous immune responses persist for a few weeks to few months, they should be able to provide some protection to the frontline health workers by immunomodulation.
SUGGESTED READING
  1. Advanced Course of Vaccinology (ADVAC). Presentation delivered at ADVAC. France: Springer;  2019.
  1. Das RR, Panigrahi I, Naik SS. The effect of prophylactic antipyretic administration on post-vaccination adverse reactions and antibody response in children: a systematic review. PLoS One. 2014;9(9):e106629.
  1. Netea MG, Joosten LAB, Latz E, Mills KHG, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.
  1. O'Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20(6):335–7.
  1. Siegrist CA. Vaccine immunology. In: Plotkin SA, Orenstein W, Offit P (Eds). Vaccines, 5th edition. Philadelphia: Saunders Elsevier;  2008. pp. 17–36.
  1. Singhal T, Amdekar YK, Agarwal RK. IAP Guidebook on Immunization, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd;  2009.
  1. Thacker N, Shendurkar N. Childhood Immunization: Issues and Options, 1st edition. New Delhi: Incal Communications;  2005.
  1. Vashishtha M. Manual of Advancing Science of Vaccinology. Mumbai: Indian Academy of Pediatrics;  2009.
  1. Vashishtha VM. Are BCG-induced non-specific effects adequate to provide protection against COVID-19? Hum Vaccin Immunother. 2020;7:1–4.