Effect of antipyretic analgesics on immune responses to vaccination

Figures & data

Table 1. Randomized Clinical Studies investigating effect of prophylactic antipyretic analgesics on postvaccination immune response.

Author Year (ref)	Design, Setting, Subjects age, N	Reported Antipyretic, schedule	Vaccine/s	Measured outcomes, immune correlates or seroprotection cut-off	Reported significant difference in antibody response
Walter 2015 (41) [Abstract]	RCT, double blind, placebo, (USA), 12–35 mo, N = 40	Acetaminophen 0, q 4–6 hrs for 24 hrs	Influenza (IIV3)	HAI ≥ 40
Wysocki 2014 (39) [Abstract]	RCT, Open label, placebo (Poland), infants, N = 800	Paracetamol^(a), Ibuprofen 0, 6–8 hrs, then q 6–8 hrs [with each vaccination]	Prevnar-13DTaP/IPV/Hib/HBV[Primary series and booster]	Pneumococcal anticapsular IgG
				Pertussis FHA andtetanus IgG	Decreased pneumococcal antibody GMCs (for 5 of 13 serotypes) with Paracetamol prophylaxis. Decreased pertussis and tetanus toxins antibody GMCs with Ibuprofen prophylaxis.
Doedeé 2014 (38)	RCT, Open label, placebo, (Netherlands), Young adults ≥18 yr, N = 496	Paracetamol Prophylaxis:0, 8, 16 hrs; Treatment: 6, 14, 22 hrs[ with first 2 vaccine doses]	Hepatitis B vaccine[3-dose series]	Anti-HBs (≥10 IU/L)	Decreased anti-HBs levels after 3^rd dose in prophylaxis group. Antibody levels were protective in all groups. No baseline antibody levels.
Prymula 2014 (36)	RCT, Open-label (Czech Republic, Italy, Hungary, Chile, Argentina), 2 mo, N = 558	Paracetamol Prophylaxis: 0, 4–6 hrs, 8–12 hrs[with each vaccination]	4 CMenB DTaP-HBV-IPV/HiB PCV7 MenC[Primary series and booster]	hSBA, Ab to fHbp, NadA, NZ OMV (titer ≥ 5) DT & TT Ab ≥0.1 IU/mL. HepB = 10 mIU/mL. Polio virus type1, 2, 3: 1:8 dilution, Pneumococcal Abs serotypes 4, 6B, 9V, 14, 18C, 19F, 23F ≥ 0.35 ug/mL, Pertussis Abs.
Prymula 2013 (35)	RCT, Open label, (Czech Republic), 31–44 mo and 40–48 mo, N = 443	None in this study (Follow up to Prymula 2009)	10-valent Pneumococcal non- typable H. influenzae protein D conjugate (PHiD-CV)	Anti-pneumococcal serotype-specific total IgG. Pneumococcal opsonophagocytic titers (opsonic titer = 8)^(b), Anti-protein D GMC Nasopharyngeal swab cultures
Prymula 2009 (9)	RCT, Open label,(Czech Republic)16 wks at enrolment, 12–15 mo at booster, N = 459	Paracetamol0, q 6–8 hr for 24 hrs [with each vaccination]	10-valent Pneumococcal non-typable H. influenzae protein D conjugate (PHiD-CV) DTaP-HBV-IPV/Hib Rotavirus[Primary series and booster]	Anti-pneumococcal IgG ≥ 0.2 μg/mL, Pneumococcal opsonophagocytic titers = 8, Anti-PRP ≥ 0.15 μg/mL, Antidiphtheria ≥ 0.1 IU/mL, Antitetanus ≥ 0.1 IU/mL, Anti-PT ≥ 5ELU/mL, Anti-FHA ≥ 5 ELU/mL, Anti-pertactin ≥ 5 ELU/mL, Anti-HBs ≥10 mIU/mL, Anti-polio ≥ 1: 8, Anti-rotavirus IgA ≥ 20 U/mL^(c)	Primary series: Decreased antibody responses to all vaccines except for Polio; decreased antipneumococcal GMCs (all 10 serotypes), protein D, anti-PRP, anti-DT, anti-TT and anti-pertactin in prophylaxis group. Booster series: Decreased GMCs for anti-pneumococcal (all except 19F), anti-tetanus, anti-protein D in prophylaxis group.
Gross 1994 (31)	RCT, Placebo(USA), 73–88 yrs, N= 80	Acetaminophen 0, q 6 hrs × 2 days	Influenza IIV3	Influenza HAI ≥ 40
Hsia 1994 (34)	RCT double-blind-placebo (USA), ≥ 65 yrs, N=281	Acetylsalicylic acid day 1,2,3,5 and 7	Influenza IIV3	Serum specific antibody for 3 Influenza strains by ELISA- 4 fold riseBlastogenic and interleukin-2 response	Increased A/Beijing influenza antibody titers (4-fold rise) among acetylsalicylic acid group compared to placebo -more marked in >75 yrs.
Chernesky 1993 (30)	RCT double-blind placebo (Canada), ≥ 65 yrs, N = 185	Acetaminophen 0, 6 hrs	Influenza IIV3	Influenza HAI ≥40
Aoki 1993 (5)	RCT, double blind, placebo, (Canada), 27–48 yrs, N = 262	Acetaminophen 0, 4, 8, 12 hours	Influenza IIV3	Influenza HAI ≥ 40 ≥, 4-fold change in serum HAI
Uhari 1988 (6)	RCT, double blind, placebo, (Finland) 5 mo, N = 233	Acetaminophen 4 hrs after vaccination	DTPDTP-IPV	Diphtheria, Pertussis, Tetanus IgG by enzyme immunoassay.
Ceuppens 1987 (33)	Double blind, placebo (Belgium), 22–26 yrs, N = 50	Piroxicam Daily, 3 days before each vaccination and 7 days after [with each vaccination]	Hepatitis B vaccine [3-dose series]	Anti-HBs >10 U/mL by RIA, Immune complexes by RIA, Lymphocyte subpopulations/activation markers/functional studies
Lafferty 1981 (32)	Open label, controlled (USA), ≥ 65 yrs, N = 40	Indomethacin Day of vaccination for 5 days	14-valent Pneumococcal polysaccharide vaccine	Antibodies to pneumococcal polysaccharides by RIA
Goodwin 1978 (26)	Open label, controlled (USA), Healthy adults N = 30	Indomethacin - 48 hrs., 0, then q 4 hrs for 12 days	Influenza IIV2	Influenza HAI	Increased antibody titers to A-Victoria (strain with high prevaccination titers). No similar increase to novel A-New Jersey strain.

^(a) Paracetamol: international nonproprietary name for acetaminophen.

^(b) Pneumococcal Opsonophagocytic titers measured by killing assay using HL60 cell line.

^(c) Anti-polio (1,2 or 3) measured by microneutralization; all other antibodies levels were measured by ELISA.

Abbreviations by cited order: N: number of study participants; RCT: Randomized Controlled Trial; IIV3: Trivalent Inactivated Influenza vaccine; HAI: Hemagglutination inhibition; DTaP: Diphtheria, tetanus and acellular pertussis vaccine; IPV: Inactivated polio vaccine; Hib: Haemophilus influenzae type B; HBV: Hepatitis B virus vaccine; FHA: filamentous hemaglutnin; GMC: geometric mean concentration; AntiHBs: anti-hepatitis B surface antigen; 4CMenB: Meningococcal type B vaccine; PCV7: Pneumococcal pentavalent vaccine ; MenC; Meningococcal vaccine type C; hSBA: Serum complement bactericidal activity; fHbp: factor H binding protein; NadA: Neisserial adhesion A; NZOMV: New Zealand strain outer membrane vesicles; DT: Diphtheria toxoid; TT: Tetanus toxoid; PRP: polyribose ribitol phosphate, a Hib antigen; ELISA: Enzyme -linked Immunosorbent Assay; IIV2: Bivalent Inactivated Influenza vaccine. RIA: Radioimmunoassay.

Table 2. Observational studies reporting antipyretics analgesics use around vaccination time.

Author Year (ref.)	Study vaccine/s, Setting, Subjects age, N	Antipyretic analgesic reported use	Measured outcomes, immune correlates or seroprotection	Results/Antibody response
Jackson 2016 (45)	Influenza (monovalent 2009 pandemic H1N1), (USA) ≥ 18 and ≤ 50 yr N= 1597	Low-dose Aspirin, self-reported chronic use by 43%	Hemagglutination-inhibition titers	Low-dose Aspirin use was not significantly associated with hemagglutination-inhibition titers.
Andrews 2011 (8)	Influenza (split virion, AS03B-adjuvanted AND non-adjuvanted whole virion H1N1 (2009), (UK) 6 mo −12 yr N= 943	Antipyretic analgesics therapeutic use: Adjuvanated 1st dose: 36.5%, 2nd dose: 28.4% Whole virion: 1st dose: 22.1%, 2nd dose: 16.6%	Hemagglutination-inhibition titers (≥ 1:32) Microneutralisation titers (≥1:40)	Paracetamol^(a) or ibuprofen use on day 0 or day 1 did not affect antibody titer after 1^st or 2^nd vaccine dose
Mills 1998 (44)	WC-DTP-IPV/RPR-T, Acellualar Pertussis, DTP-IPV/RPR-T, (Canada) ≥ 2 and <3 mo infants N=560	Acetaminophen prophylaxis use among 3 sites (93.4%, 80.6% and 53.8% and increased to 97.0%, 93.0% and79.8%, respectively after therapeutic use in first 24 hrs	Anti-PRP 20.15 and 2 1.0 ug/ml. Polio types 1, 2 and 3 neutralizing antibody titers ≥ 8. DT Ab levels ≥ 0.01, ≥ 0.10 and 1.0 IU/mL. TT Ab levels ≥ 0.01, ≥ 0.10 and ≥ 1.0 EU/ml. Pertussis agglutination titer ≥ 64. Pertussis Ag responses ≥ 25 and ≥ 100 EU/mL.	Acetaminophen prophylaxis did not affect immunogenicity. Differences in antibody responses clinically insignificant (tetanus seroprotection is 100%, diphtheria 99%).
Marcinak 1993 (43)	DTaP, WC-DTP, (USA) 15 – 20 mo N=246	Acetaminophen therapeutic use 63% in WC-DTP, 31% in DTaP	PT Abs using CHO cell assay FHA and PT Abs by ELISA, TT by ELISADT by VERO cell assay	FHA, PT and functional PT were higher in acellular DTP compared to whole cell even in subgroup analysis by race, gender, and practice setting. Antipyretics use reported but not analyzed for correlation with antibody response.
Auerbach 1992 (42)	WC-DTP, Acellular DTP, (USA) 15–24 mo, 4–6 yr N=111	Acetaminophen use 53% in WC-DTP, 12% acellular DTP	Pertussis agglutinin (1:2 lower limit of detection). PT Ab by toxin neutralization. DT & TT ( ≥ 0.01 IU/mL considered protective).	No differences in antibody responses between the 2 doses of acellular DTP. All 3 groups had significant increases in pertussis agglutinins, but higher GMT for acellular DTP
Long 1990 (7)	WC-DTP, (USA)2 mo,N=538	Acetaminophen therapeutic use 73.5% within 48 hr in DTP, 21% in placebo. DTP prophylactic use 2.1%.	DT Ab assay by toxin neutralization. Tetanus toxoid Ab by hemagglutination. Pertussis Ab by direct cell agglutination and by toxin neutralization.	Acetaminophen use did not correlate with Pertussis antibody response.

^(a) Paracetamol: international nonproprietary name for acetaminophen.

Abbreviations by cited order N: number of study participants; WC: Whole Cell; DTP: Diphtheria, tetanus, pertussis vaccine; IPV: Inactivated polio vaccine; RPR polyribose ribitol phosphate; T: tetanus vaccine; DT: Diphtheria toxoid; TT: tetanus toxoid; DTaP: Diphtheria, tetanus, acellular pertussis vaccine; FHA: filamentous hemaglutnin.

Figure 1. Antipyretics analgesics inhibition of post-vaccination immune response. This figure illustrates the different mechanisms by which antipyretic analgesics might inhibit post-vaccine adaptive immune response as suggested by the referenced studies. Vaccine antigen delivered at injection site induces immune and inflammatory mediators which triggers leukocyte migration and activates dendritic cells (DC) [upper left]. DCs capture, process and present antigen to naive CD4 T cells and induce their proliferation and differentiation into T-helper cells (Th0). Th0 influenced by cytokines and other stimuli differentiate into T-helper subsets Th1 (associated with cellular responses) and Th2 (associated with humoral responses). Th2 cells interact with B cell and secrete cytokines (IL4, IL5, IL13) leading to B cell proliferation and differentiation into antibody-secreting plasma cells and memory B cells. Insert: Major intracellular signaling pathways that lead to activation of nuclear factors and expression of cellular end products. PKC: Protein Kinase C; NF-kB: Nuclear factor κ B; NFAT: Nuclear factor of activated T-cells; ERK: extracellular signal regulated kinases; JNK: Jun N terminal kinase; MAPK: mitogen-activated protein kinase; ATF2: Activating transcription factor-2; Cox-2: Cyclo-oxygenase 2; Bcl-XL: B lymphocyte; BLIMP-1:B lymphocyte induced maturation protein-1; XBP-I: X-box-binding protein1.