Specific antibody titers against various infectious agents in polyspecific human immunoglobulin preparations

Transcription

1 Specific antibody titers against various infectious agents in polyspecific human immunoglobulin preparations Global Bio Conference 2018 Hye-Kyung Cho Department of Pediatrics, Gachon University College of Medicine, Gil Medical Center, Incheon, Republic of Korea

2 Contents Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

3 Contents Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

4 Immunoglobulin preparations Derived from pooled plasma of adults Primarily of the immunoglobulin (Ig) fraction (at least 90% IgG and trace amounts of IgA and IgM) IMIG is a concentrated protein solution (approximately 16.5% or 165 mg/ml) IVIG is available as a lyophilized powder or as a formulated liquid solution, with final concentrations of IgG ranging from 3% to 12%, depending on the product.

5 Antibodies included in IG preparations Derived from pooled plasma of healthy donors 1,000 to 60,000 per lot of final product Include broad spectrum of antibodies Supply a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic, and mycoplasmal agents, and their toxins

6 Classification of IG products Formulation by type of antibody desired, donor Polyspecific (polyvalent) IG Specific (hyperimmune) IG: eg., HBIG, VZIG, HRIG, TIG, Formulation by route of administration IVIG (intravenous) IMIG (intramuscular) SCIG (subcutaneous)

7 Contents Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

8 Indications of IG use in infectious diseases Replacement therapy in antibody-deficiency disorders Prophylaxis against some viral infections Proven beneficial only for measles, varicella, hepatitis A, hepatitis B Treatment of some infectious diseases AAP. Redbook 30 th ed, 2015 Looney RJ et al. Best Pract Res Clin Haematol. 2006

9 Primary Immunodeficiencies Antibody-mediated Immune deficiency Cell-mediated Immune deficiency Combined immune deficiency Phagocytic deficiency Complement deficiency Complement 2% Phagocytic Cellular 18% Antibody 10% 50% Others Combined 20% The overall prevalence of PID is about 1:100,000

10 Primary immunodeficiencies: Ab deficiencies Disorder Gene (if known) IgG replacement indicated? IVIG every 3 4 weeks are effective in preventing serious Agammaglobulinemia bacterial infections. X-linked agammaglobulinemia Btk Yes μ heavy chain deficiency IGHM Yes Lifelong IVIG treatment should be needed. Igα deficiency CD79A Yes Igβ deficiency CD79B Yes B-cell linker protein BLNK Yes Common variable immune deficiency Immune co-stimulator protein ICOS Yes CD19 deficiency CD19 Yes CD20 deficiency CD20 Yes TACI deficiency TNFRSF13B Yes BAFF receptor deficiency TNFRSF13C Yes CVID Unknown Yes Kobrynski L. Biologics 2012

11 Primary immunodeficiencies: Ab deficiencies Disorder Gene (if known) IgG replacement indicated? Other antibody deficiencies Selective IgA deficiency Unknown No IgG subclass deficiency Unknown If recurrent infections Specific antibody deficiency Transient hypogammaglobulinemia of infancy Other PIDD with antibody deficiency Unknown Unknown Hyper-IgM syndrome (X-linked) CD40L Yes (AR) AID, UNG Yes Severe combined immune deficiency Various Yes Wiskott Aldrich syndrome WASP Yes To ensure IG potency in the PI patients is crucial! Ataxia-telangiectasia syndrome ATM Yes Reticular dysgenesis AK2 Yes DiGeorge syndrome 22q11.2/10p13 deletion Only for patients with low IgG Kobrynski L. Biologics 2012

12 Contents 1 Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

13 U.S. FDA regulations on antibody potency of IG products (CFR 21) Antibody levels and tests Each lot of final product shall contain at least the minimum levels of antibodies for diphtheria, measles, and for at least one type of poliomyelitis. Minimum antibody levels No less than 2 units of diphtheria antitoxin per ml. Measles neutralizing antibody level, compared with that of a reference material designated by the Center for Biologics Evaluation and Research (CBER), FDA Poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody level, compared with that of a reference material

14 European regulations on antibody potency of IG products Product specific for SC/IMIG with a minimum antibody content for Hepatitis A virus of 100 IU/ml No recommended routine measurement for measles antibody EMEA. Guideline on Core SPC for Human Normal Immunoglobulin for Subcutaneous and Intramuscular Use 2015.

15 Antibodies included in IG preparations The production of protective antibodies in human plasma is initiated via vaccination or natural exposure. Changes on epidemiology of various infectious diseases and herd immunity Improvements in sanitation and socioeconomic conditions, widespread use of vaccines, high immunization rate Decreased natural boosting from exposure to wild-type pathogens Limitation to maintain protective antibody level, possible waning immunity

16 Contents 1 Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

17 Potency of measles neutralizing antibodies in 7 IGIV products manufactured IVIG from Source Plasma (white bars), IVIG from recovered plasma (shaded bars) *P <.05, compared with US Reference IG (US Ref IG); **P <.05, for comparison of the 2 donor groups. Audet S, et al. JID 2006;194:781-9.

18 Global reported measles cases and estimated coverage with the first and second dose of measles-containing vaccine by year ( ) Rota PA et al. Nat Rev Dis Primers Jul

19 Vaccine-induced Ab vs. Natural infection-derived Ab Abs derived from vaccines are lower in level and shorter in duration than antibodies obtained from natural infection. IgG avidity and IgG antibody levels, important parameters of the quality of humoral immune response, are lower after vaccination than after primary infection. Recent infection IgG avidity IgG avidity IgG level Recent vaccination IgG level (A) Anti-rubella Ab kinetics for recent vaccination (B) for recent primary rubella virus infection Vauloup-Fellous C, Grangeot-Keros L. Clin Vaccine Immunol 2007

20 Ab level in plasma pool Declining antibody titer in plasma pool Before the measles vaccine was introduced in 1963 (1965 in Korea), the general population was exposed to measles naturally, resulting in a high level of antibodies for the disease. Natural exposure Vaccination 1960 s time

21 Contents 1 Characteristics of immunoglobulin preparations Indication of IG use in infectious diseases Standards of antibody potency Declining antibody titer in plasma pool Changes on prophylatic dosage of IG

22 Measles High fever and rash 3C (cough, coryza, conjunctivitis) Very contagious Airborne transmission Measles vaccines: WHO position paper April 2017

23 Disease burden of measles The global annual reported measles incidence declined by 75% during ; from 146 to 35 cases per million population Estimated 134,200 measles deaths globally in 2015 Estimated 7 million people affected by measles in 2016 Case fatality: <0.01% in industrialized countries, >5% in developing countries Measles vaccines: WHO position paper April 2017 Rota PA et al. Nat Rev Dis Primers Jul

24 Post-exposure prophylaxis (PEP) against measles Use of vaccine if given within 72 hours of measles exposure to susceptible individuals, will provide protection or disease modification in some cases Use of Immunoglobulin Can be administered either IM or IV within 6 days of exposure to prevent or modify measles should be given as soon as possible after exposure IG should be considered for susceptible pregnant women susceptible immunocompromised contacts of measles children less than 6 months of age AAP. Redbook 30 th ed, 2015

25 IG for measles post-exposure prophylaxis : Japan experience 33 unvaccinated infants given IGIM (0.33 ml/kg) within 5 days of measles exposure ( >1 h in same room) Neutralizing antibody concentrations determined in IGIM lots Measles attack rates were: 8/14 (57%) among infants given IGIM with 16 IU/mL (5.28 IU/kg) 1/6 (17%) among infants given IGIM with 33 IU/mL (10.89 IU/kg) 0/13 (0%) among those given IGIM with 40 or 45 IU/mL (13.2 IU/kg) Protected children received a mean dose of 10.9 IU/kg compared to 5.7 IU/kg for whom PEP failed. Endo A, et al. J Pediatr. 2001;138:926-8.

26 Lowering measles specification for IVIG/SCIG Evidence for declining antibody titers Concern for supply failure of release testing results in rejection of IVIG/SCIG lot Concern for primary immunodeficiency patients will protective titers be achieved? 2007, U.S. FDA, Blood Products Advisory Committee IVIG/SCIG, 0.60 x CBER 0.48 x CBER * IMIG, 0.60 x CBER standard

27 Calculated serum measles-neutralizing Ab (mnab) concentration following IG PEP IG Product (Dose) IGIM (0.25ml/kg) IGIM (0.50 ml/kg) IGIV (100 mg/kg) IGIV (200 mg/kg) IGIV (400 mg/kg) Minimum mnab potency (IU/mL) Minimum mnab dose (IU/kg) Calculated serum mnab level (miu/ml) Peak 4-6 hours Equilibrium 4-5 days Trough days [158] [315]

28 IG for measles PEP The recommendations for the use of immunoglobulin products for measles post-exposure prophylaxis were revised in the US in These revised doses of immunoglobulin for measles PEP have been increased from previous recommendations due to a recognition that measles antibody levels have declined over recent years. This is likely due to a much higher proportion of donors with vaccine-only associated measles immunity.

29 Recommended IG dosage for measles PEP Indications Dose Interval before MMR vaccine administration Infants <12months of age Susceptible immunocompetent contacts <30 kg Pregnant women without evidence of immunity Severely immunocompromised persons* 0.5 ml/kg IM (max dose = 15mL) 0.5 ml/kg IM (max dose = 15mL) 6 months 6 months 400 mg/kg IV 8 months and nonpregnant 400 mg/kg IV 8 months AAP. Redbook 30 th ed, 2015

30 PRN titer (IU/mL) Potency of measles neutralizing Abs in IG products (1% IgG concentration) IGIV IGIM IGSC Minimum potency of IGIM Minimum potency of IGIV, IGSC 0.0 A B C D E A F G H I IV IM SC Immunoglobulin Products Kim KH et al. 2015

31 mnab potency in IGIV and IGSC products -Korean study- Route Plasma source Manufacturer mnab potency (IU/mL) Administration dose of IG (IU/kg)* IV Korea A Korea B Japan C D US E SC Germany I IM Korea A Japan F *Administration dose - IM: 0.50mL/kg, IV: 400mg/kg, SC: 200mg/kg G H Kim KH et al. 2015

32 Acute viral hepatitis Hepatitis A (HAV) Fever, malaise, nausea and abdominal discomfort, followed by jaundice a few days later More severe in adults, full recovery may take several months Case-fatality: greater than 2% for those over 40 years of age about 4% for those aged 60 years

33 Hepatitis A, countries or areas at risk

34 Preexposure-prophylaxis of HAV for travelers (to countries with high or intermediate endemicity) Age Younger than 12 mo Recommended prophylaxis IMIG Up to 3 mo of travel, 0.02 ml/kg 3 mo of travel, 0.06 ml/kg (repeat every 5 months) 12 mo through 40 y HepA vaccine 41 y or older HepA vaccine, with or without IMIG Modified from AAP. Redbook 30 th ed, 2015

35 PEP against HAV Time since exposure Age of patient 2 wk Younger than 12 mo 12 mo through 40 y 41 y or older People of any age who are immunocompromised, have chronic liver disease, or contraindication to vaccination > 2 wk Younger than 12 mo 12 mo or older Recommended prophylaxis IMIg, 0.02 ml/kg HepA vaccine IMIG, 0.02 ml/kg, but HepA vaccine can be used if IGIM is unavailable IMIG, 0.02 ml/kg No prophylaxis No prophylaxis, but HepA vaccine may be indicated for ongoing exposure AAP. Redbook 30 th ed, 2015

36 Reported No. of Cases Epidemiology of HAV Republic of Korea, United States, Year

37 Age specific seroprevalence against hepatitis A in Korea, Lee H et al. J Korean Med Sci 2011

38 Evaluation of potencies of IG products against HAV Anti-HAV Ab levels are declining in plasma donors from developed countries. The content of anti-hav IgG and neutralizing Abs was measured by an immunoassay and an end point dilution antibiotic resistance titration assay. Daily decay of plasma anti-hav antibodies was modeled assuming a best-case scenario of complete absorption of 0.02 ml/kg of IG (intramuscular). Tejada-Strop A et al. JAMA Intern Med. 2017

39 Tejada-Strop A et al. JAMA Intern Med. 2017

40 TABLE. Indications and updated dosage recommendations for GamaSTAN S/D human immune globulin for preexposure and postexposure prophylaxis against hepatitis A infection Indication Updated dosage recommendation Preexposure prophylaxis Up to 1 month of travel Up to 2 months of travel 2 months of travel or longer 0.1 ml/kg 0.2 ml/kg 0.2 ml/kg (repeat every 2 months) Postexposure prophylaxis 0.1 ml/kg Nelson NP. MMWR 2017;66(36):

41 Anti-HAV titers in intramuscular IG products -Korean study- Route Plasma source Manufacturer Anti-HAV (IU/mL) IM Korea A 19.7 Japan F 5.5 G 5.5 H 5.5 *Hepatitis A (anti-hav titer) Electrochemiluminescence immunoassay, Cobas 8000 e602 (Roche, Germany) minimum protective level, 10 miu/ml Cho HK et al. presented at Autumn Meeting of KPID, 2014

42 Korea 28.2 Tejada-Strop A et al. JAMA Intern Med. 2017

43 Korea 42.5 Tejada-Strop A et al. JAMA Intern Med. 2017

44 Lee S et al. Transfusion 2017

45 Expected trough levels for Hib, four serogroups of meningococcus in 16 lots of IVIG products from Korea *IVIG 400 mg/kg was assumed to be infused into the patients. Lee S et al. Transfusion 2017

46 Expected trough levels of OIs against 26 serotypes of pneumococci in various IVIG products *IVIG 400 mg/kg was assumed to be infused into the patients. Lee S et al. Transfusion 2017

47 Considering issues Is an antibody potency test for all pathogens absolutely necessary? Serostatus of population (declining antibody titers) Epidemiology of infectious disease Concern for supply Costs Development of efficient and accurate test tools

48 Subcutaneous IG (SCIG) IVIG every 3 4 weeks are effective in preventing serious bacterial infections and improving the quality of life for treated patients. Administration of SCIG is equally effective in preventing infections and has a lower incidence of serious adverse effects compared to IVIG. The tolerability and acceptability of SCIG has been demonstrated in numerous studies showing improvements in quality of life and a preference for SCIG therapy in patients with antibody deficiencies. Nevertheless, SCIG is NOT available in Korea.

49 Conclusions It is important that various formulations of immunoglobulins are supplied stably to properly respond to various situations and treat patients. Continuous monitoring and quality control of antibody levels in IG preparations is essential for the effective prevention and treatment of infectious diseases. In order to establish appropriate quality control standards, sufficient discussion of clinical physicians, infectious disease epidemiologists, manufacturers, and biopharmaceuticals authorities is required.