Immunogenicity of plasma-derived hepatitis B vaccine

Journal of General Internal Medicine, Jul 2013

Stanely M. Lemon, Davis J. Weber

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Immunogenicity of plasma-derived hepatitis B vaccine

JOURNALOFGENERALINTERNALMEDICINE lmmunogenicity of Plasma-derived Hepatitis B Vaccine: Relationship to Site of Injection Obesity - A HUNDREDYEARSh a v e e l a p s e d since Louis Pasteur a d m i n i s t e r e d the first rabies virus vaccine to y o u n g Joseph Meister. Since then, enormous strides h a v e taken place in our ability to immunize a g a i n s t p a t h o g e n i c viruses a n d bacteria. More a n d more sophisticated i m m u n o g e n s h a v e b e e n developed. The crude rabbit spinal cord preparation of Pasteur h a s given w a y to well-characterized a t t e n u a t e d virus vaccines a n d purified, inactivated immunogens. Active immunization a g a i n s t hepatitis B virus represents the latest chapter in the a n n a l s of virus vaccines, a n d r e m a i n s a fast-moving field. New vaccines are on the horizon, including one b a s e d on the use of hepatitis B virus surface a n t i g e n (HBsAg) expressed by a n d extracted from yeast cells into which the related virus g e n e s e q u e n c e h a d been introduced a s recombinant DNA.~ For several years, however, a licensed hepatitis B vaccine h a s been a v a i l a b l e which is produced from HBsAg-containing h u m a n p l a s m a through a complex process involving multiple purification a n d inactivation steps. 2 Early clinical trials with this hepatitis B plasma vaccine d e m o n s t r a t e d that it w a s both safe a n d effective. Intramuscular doses of 20 to 40 ~g of alumadsorbed antigen elicited serum antibody (anti-HBs) responses that were d e t e c t a b l e by solid-phase imm u n o a s s a y in 85-95% of h e a l t h y h o m o s e x u a l males.3. 4 Such a n t i b o d y responses correlated with a high degree of protection a g a i n s t symptomatic infection. However, w h e n the hepatitis B vaccine w a s given in r e c o m m e n d e d doses to hospital workers, under conditions of e v e r y d a y use, several groups of investigators found that a s few a s 50-70% of surv e y e d i n d i v i d u a l s h a d s i g n i f i c a n t a n t i b o d y responses, s-9 These studies m a y h a v e b e e n flawed. They were retrospective. Also, in some c a s e s postimmunization a n t i b o d y screening m a y not h a v e been carried out until up to one y e a r after completion of the r e c o m m e n d e d three-dose course of vaccine. By t h i s t i m e , a n t i b o d y l e v e l s m a y h a v e d e c l i n e d s o m e w h a t from t h e m a x i m u m l e v e l s a c h i e v e d f o l l o w i n g i m m u n i z a t i o n . N o n e t h e l e s s , t h e s e studies s u g g e s t a poorer response to the vaccine under field conditions t h a n the controlled clinical trials u n d e r relatively ideal conditions would h a v e predicted. These poor results cannot be attributed to impaired vaccine potency or to improper s t o r a g e (for example, i n a d v e r t a n t freezing of the vaccine prior to its administration). 7 However, retrospective reviews carried out by the vaccine m a n u f a c t u r e r a n d the Centers for Disease Control s u g g e s t that the site of i n t r a m u s c u l a r injection is a n important factor in d e t e r m i n i n g the a n t i b o d y response to the vaccine. 7 In the CDC study, a m o n g m e d i c a l centers a d m i n i s t e r i n g vaccine by injection into the buttocks, postimmunization anti-HBs developed in 82% of recipients. In contrast, the a v e r a g e vaccine response w a s 93% in centers that a d m i n i s t e r e d vaccine m a i n l y by deltoid injection. Why should it matter w h e t h e r vaccine is administered by buttocks or deltoid injection? The ans w e r is u n c e r t a i n . H o w e v e r , a h y p o t h e s i s is s u g g e s t e d by a n e x a m i n a t i o n of the e a r l y events surrounding the initial i m m u n e response to a n antigen, a n d the m e c h a n i c a l factors involved in att e m p t e d i n t r a m u s c u l a r i n j e c t i o n in t h e g l u t e a l region. Usually, in the earliest s t a g e s of a n t i b o d y induction, foreign a n t i g e n s must be processed by m a c r o p h a g e s or similar cells before they a r e presented to T a n d B lymphocytes.~° This processing of the immunogen, which involves p h a g o c y t o s i s a n d partial d e g r a d a t i o n , renders it m u c h more imm u n o g e n i c a n d results in the r e l e a s e of interleukin I by the involved m a c r o p h a g e s . It is the initial step in a complex series of events involving several types of i m m u n e effector cells a n d lymphokines. The end result of this process is the recruitment a n d selective amplification of specifically reactive lymphocytes a n d their subsequent differentiation to p l a s m a cells secreting reactive antibody. Thus, for most p a r e n t e r a l l y a d m i n i s t e r e d i m m u n o g e n s to work effectively, i m m u n o g e n i c m a t e r i a l must be delivered in a m a n n e r that will facilitate p h a g o c y t o s i s a n d processing by the fixed macrophage or related cells. Alum a d j u v a n t s m a y work in this way; alum-adsorbed a n t i g e n is relatively p a r t i c u l a t e a n d thus more readily processed by the m a c r o p h a g e . The site at which i m m u n o g e n s are adminst e r e d c o u l d i n f l u e n c e s u b s e q u e n t a n t i b o d y response, for related reasons. Given the thickness of g l u t e a l a d i p o s e tissue, most a t t e m p t s to a d m i n i s t e r vaccine into muscle by buttocks injection i n s t e a d deliver the vaccine into a d i p o s e tissue. 1~We would expect that good sites for injection of vaccines would be those (such a s muscle) from which injected antigens p a s s rapidly through the blood to the s p l e e n or through l y m p h a t i c s to l y m p h nodes w h e r e proce s s i n g m a y occur. On the other h a n d , subcutan e o u s a d i p o s e tissue m a y be a poor site for vaccine injection b e c a u s e of slow mobilization of antigen. EDITORIALS This observation m a y partly explain the failure of hepatitis B p l a s m a v a c c i n e to elicit good a n t i b o d y r e s p o n s e s w h e n a d m i n i s t e r e d b y gluteal injection. There is e v i d e n c e to support this hypothesis. Recently, w e a n d our c o l l e a g u e s found that a high w e i g h t - h e i g h t index (a marker of obesity) correlated with a lack of a n t i b o d y r e s p o n s e following injection of the hepatitis B v a c c i n e into the buttocks. 9 Only 29.5% of hospital e m p l o y e e s w h o s e w e i g h t - h e i g h t indices w e r e a b o v e the s e x - a d j u s t e d 75th percentile for all Americans h a d d e t e c t a b l e levels of anti-HBs e l e v e n months after completing the v a c c i n e series. O n the other hand, a n t i b o d y w a s present in 63.3% of e m p l o y e e s w h o s e w e i g h t height indices w e r e b e l o w the 75th percentile (p < 0.01). These results might b e e x p l a i n e d by a greater d e g r e e of difficulty in a c h i e v i n g true intramuscular delivery of vaccine b y buttocks injection in o b e s e individuals. However, site of injection might not e x p l a i n all of the problem. A r e v i e w of the a n a t o m y s u g g e s t s that the majority of "intramuscular" buttock injections end up in a d i p o s e tissue, e v e n in n o n - o b e s e persons, n So t h e s e results could also s u g g e s t that mobilization of v a c c i n e from a d i p o s e tissue is relatively i m p a i r e d in o b e s e individuals. We recently d e t e r m i n e d that a high w e i g h t height index m a y a l s o predict a lack of a n t i b o d y r e s p o n s e to hepatitis B vaccine e v e n w h e n it w a s given by long n e e d l e s into the deltoid muscle, an injection p r o c e d u r e which should result in vaccine deposition in muscle.12 A similar finding h a s b e e n reported by others.13 The e x p l a n a t i o n for t h e s e observations r e m a i n s obscure. Poor v a c c i n e r e s p o n s e r a t e s a m o n g s o m e groups receiving v a c c i n e p r e d o m i n a n t l y by deltoid injection 7. 12,15 hint at other factors, in addition to obesity, that m a y influence the immunogenicity of this vaccine in everyday usage. Advancing a g e and male sex m a y a d v e r s e l y affect r e s p o n s e to the vaccine. 14 I m m u n o c o m p r o m i s e d persons, such a s hem o d i a l y s i s p a t i e n t s , m a y h a v e m e a s u r a b l y impaired a n t i b o d y r e s p o n s e s . Certain major histocompatibility complex markers ~5 or i m p a i r e d B cell r e s p o n s i v e n e s s to p o k e w e e d mitogen in vitro 16 might b e a s s o c i a t e d with a poor a n t i b o d y r e s p o n s e following administration of the hepatitis B vaccine. Clearly, m a n y q u e s t i o n s r e m a i n a n d there is n e e d for further work in this area. Intramuscular injection m a y not b e optimal for all non-replicating i m m u n o g e n s . An alternative injection site, such a s skin, m a y s o m e t i m e s b e better. Intradermal injection of hepatitis B virus vaccine a n d r a b i e s v a c c i n e h a s b e e n s h o w n to e n h a n c e their i m m u n o g e n i c i t y J 7-20 In a r e c e n t l y r e p o r t e d , c o n t r o l l e d , b l i n d e d study, intradermal injection of 2 ~g (one tenth the normal dose) of hepatitis B p l a s m a v a c c i n e resulted in s o m e w h a t r e d u c e d but p r o b a b l y accepta b l e a n t i b o d y levels c o m p a r e d with t h o s e a c h i e v e d with f u l l - d o s e , i n t r a m u s c u l a r i n j e c t i o n of vaccine.J9 Similarly, intradermal immunization with 0.1 ml h u m a n diploid cell r a b i e s v a c c i n e p r e p a r e d by the Merieux Institute (also o n e tenth the normal, intramuscular dose) results in a n t i b o d y levels that are a c c e p t a b l e for p r e - e x p o s u r e (but not post-exposure) prophylaxis. 2°,21It h a s b e e n s u g g e s t e d that the a p p a r e n t e n h a n c e m e n t of i m m u n o g e n i c i t y of vaccine given by intradermal injection m a y b e d u e to efficient u p t a k e a n d p r o c e s s i n g of a n t i g e n by Langerhans' cells within the epidermis.19 Although the p h e n o m e n o n is not restricted to hepatitis B a n d rabies vaccines, it h a s particular, practical implications for immunization a g a i n s t t h e s e two dise a s e s . Successful immunization with r e d u c e d d o s e s of vaccine given intradermally m a y provide a significant cost s a v i n g s of t h e s e two, particularly expensive, vaccines. Moreover, the administration of smaller amounts of vaccine by the intradermal route m a y permit limited v a c c i n e q u a n t i t i e s to b e s p r e a d a m o n g a larger n u m b e r of people. A problem with intradermal administration, however, is that particular care must b e t a k e n to e n s u r e that vaccine g i v e n b y this route is not inadvertently administered subcutaneously. This m a y t a k e s o m e p r a c t i c e . In a n y c a s e , i n t r a d e r m a l administration of the hepatitis B v a c c i n e is still experimental. The recent e x p e r i e n c e with the hepatitis B vaccine should h u m b l e all of us. It d e m o n s t r a t e s that a p p a r e n t l y trivial differences b e t w e e n experimental a n d field conditions m a y b e of s u b s t a n t i a l practical i m p o r t a n c e . N o n e t h e l e s s , w h e n g i v e n b y deltoid injection, a s currently r e c o m m e n d e d , ~ the p l a s m a - d e r i v e d hepatitis B v a c c i n e is u s u a l l y very effective in the hospital setting, w h e r e hepatitis B infection r e m a i n s a n important o c c u p a t i o n a l hazard. 22We should not b e d i s s u a d e d from its u s e in persons at high risk for hepatitis B. High-risk workers who h a v e a l r e a d y received three injections of the hepatitis B v a c c i n e b y gluteal injection w o u l d benefit from testing for anti-HBs. Of those w h o h a v e r e m a i n e d seronegative, most (90%) will d e v e l o p detectable anti-HBs following a n a d d i t i o n a l two 1-ml d o s e s of v a c c i n e given b y i n t r a m u s c u l a r injection into the deltoid m u s c l e (Weber et al., u n p u b l i s h e d data). - - Stanley M. Lemon, MD, and David J. Weber, MD, MPH, Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina The General Internist and Occupational Medicine IMAGINEthat the scope of g e n e r a l i n t e r n a l m e d i c i n e s u d d e n t l y d o u b l e d , c r e a t i n g a p l e t h o r a of n e w res e a r c h topics, practice opportunities, a n d chall e n g i n g c a s e s . I m a g i n e t h a t a d e m o g r a p h i c shift suddenly m e a n t that large numbers of young adults n e e d e d p r i m a r y care services a n d g a v e the problems of geriatrics a n e w d i m e n s i o n . I m a g i n e that a n e w a n d different a p p r o a c h to d i s e a s e p r e v e n t i o n a n d h e a l t h promotion o p e n e d itself to the internist. There is a field of m e d i c i n e t h a t holds out such exciting possibilities. It exists l a r g e l y in the shadows of m e d i c a l practice, visible to g e n e r a l internists only in fleeting g l i m p s e s yet affecting most of their p a t i e n t s from y o u n g a d u l t h o o d a n d adolescence to well b e y o n d r e t i r e m e n t a g e . It is a discipline of m e d i c i n e t h a t o v e r l a p s m u c h of g e n e r a l internal medicine in content yet incorporates highly specialized k n o w l e d g e a n d a p p r o a c h e s to solving problems. It is a m o d e of m e d i c a l practice t h a t involves u n i q u e a n d often difficult c h a l l e n g e s but c o n t a i n s e l e m e n t s of practice that most internists u s e every d a y . It is a distinct m e d i c a l s p e c i a l t y in form a n d content but one with so few c r e d e n t i a l e d specialists that internists now a n d for years to come will h a n d l e more c a s e s in the s p e c i a l t y t h a n the s p e c i a l i s t s t h e m s e l v e s . This b r a n c h of m e d i c i n e is o c c u p a t i o n a l medicine, a n d it is full of opportunity for g e n e r a l i n t e r n a l m e d i c i n e . ~.2 This is so b e c a u s e o c c u p a t i o n a l medicine, like i n t e r n a l medicine, is c o n c e r n e d with a d u l t s , both w h i l e t h e y are of w o r k i n g a g e a n d into their retirement. Most a d u l t s s p e n d a third of their w a k i n g hours at work, a n d social psychologists h a v e shown t h a t work (or the lack of it) is a critical e l e m e n t in a person's life, identity, a n d self-esteem. 3'4 This is a n a s p e c t of the p a t i e n t ' s life t h a t the g e n e r a l internist c a n ill afford to ignore, b e c a u s e work p l a y s a n important role in h e a l t h a n d the p a t i e n t ' s h e a l t h h a s important i m p l i c a t i o n s for work. The o r g a n i z e d s p e c i a l t y of o c c u p a t i o n a l medicine is now at a c r o s s r o a d s - - a c t u a l l y a crisis - b e c a u s e the s u p p l y of t r a i n e d a n d i n t e r e s t e d phys i c i a n s falls far short of d e m a n d . 5 A g r e a t e x p a n sion in the d e m a n d for occupational h e a l t h services h a s led to a m u c h g r e a t e r i n v o l v e m e n t of other m e d i c a l s p e c i a l i s t s a n d of p r i m a r y care practitioners, i n c l u d i n g internists. After m o n t h s of d e l i b e r a t i o n , the A m e r i c a n C o l l e g e of P h y s i c i a n s in 1984 a d o p t e d a position p a p e r on the internist a n d o c c u p a t i o n a l m e d i c i n e . 6 This important paper, s u m m a r i z e d in the November 1984 i s s u e of the ACP Observer, e m p h a s i z e s two m a i n points: Internists s h o u l d be r e s p o n s i v e to the o c c u p a t i o n a l h e a l t h n e e d s of their p a t i e n t s a n d s h o u l d be p r e p a r e d to i d e n t i f y o c c u p a t i o n a l l y a s s o c i a t e d disorders a n d h e a l t h concerns. Physic i a n s are a l s o j u d g e d to h a v e a r e s p o n s i b i l i t y to improve h e a l t h s t a n d a r d s b y s u p p o r t i n g a n d part i c i p a t i n g w h e r e p o s s i b l e in the p r e v e n t i o n of occ u p a t i o n a l d i s o r d e r s . The i n t e r n i s t s ' r o l e in 1. Scolnick EM. McLean AA , West DJ , McAleer WJ , Miller WJ , Buynak EB. Clinical evaluation in healthy adults of a hepatitis 13vaccine made by recombinant DNA . JAMA 1984 ; 251 : 2812 - 5 2. Centers for Disease Control, Immunization Practices Advisory Committee . Recommendations for protection against viral hepatitis . MMWR 1985 ; 34 : 313 - 35 3. Szmuness W , Stevens CE , Zang EA , Harley EJ , Kellner A . A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report . Hepatology 1981 ; 1 : 377 - 85 4. Francis DP , Hadler SC , Thompson SE , et al. The prevention of hepatitis B with vaccine . Report of the Centers for DiseaseControl multi-center efficacy trial among homosexual men . Ann Intern Med 1982 ; 97 : 362 - 6 5. Rumley RL , Chapman SW . Hepatitis B vaccination of high-risk hospital employees and hemodialysis patients . Abstracts of the 1984 lnterscience Conference on Antimicrobial Agents and Chemotherapy , Washington, D.C. October 1984 ; p 104 6. Schaaff DM , Lender M , Snedeker P , Graham LA . Hepatitis B vaccine in a hospital . Ann Intern Med 1984 ; 101 : 720 - 21 7. Centers for DiseaseControl. Suboptimal response to hepatitis B vaccine given by injection into the buttock . MMWR 1985 ; 34 : 105 - 13 8. Pead PJ , SaeedAA, Hewitt WG , Brownfield RN . Low immune responses to hepatitis B vaccine among healthy subjects . Lancet 1985 ; 1 : 1152 9. Weber DJ , Rutala WA , Samsa GP , Santimaw JE , Lemon SM . Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine . JAMA 1985 ; 254 : 3187 - 9 10. Joklik WK , Willett HP , Amos DB (eds). Zinsser microbiology. Norwalk , Cn: Appleton-Century-Crofts , 1984 11. Cockshott WP , Thompson GT , Howlett LJ , Seeley ET . Intramuscular or intralipomatous injections . N Engl J Med 1982 ; 307 : 356 - 8 12. Weber DJ , Rutala WA , Samsa GP , Bradshaw SE , Lemon SM . Obesity, not site of immunization, is the key predictor of a poor antibody response to the hepatitis B plasma vaccine . Submitted for publication. 13. Lane TW , Tashjian LS. lvey F , Gerner H , Via BE . Immunogenicity of hepatitis B vaccination in hospital employees: predicators of seroconversion . Abstracts of the 1985 Interscience Conference on Antimicrobial Agents and Chemotherapy , Minneapolis, October 1985 , p 94 14. Jacobson IM , Dienstag JL . Viral hepatitis vaccines . Annu Rev Med 1985 ; 36 : 241 - 61 15. Craven DM , Kunches LM , Dienstag JL , et al. Analysis of nonresponsiveness to hepatitis B vaccine in health care workers . Hepatology 1984 ; 4 : 1077 16. Nowicki MJ , Tong MJ , Bohman RE . Alteration in the immune response of nonresponsers to the hepatitis B vaccine . J Infect Dis 1985 ; 152 : 1245 - 8 17. Miller KD , Gibbs RD , Mulligan MM , Nutman TB , Francis DP . lntradermal hepatitis B vaccine: immunogenicity and side-effects in adults . Lancet 1983 ; 2 : 1454 - 6 18. Zoulek G , Lorbeer B , Jilg W , Dienhardt F . Evaluation of a reduced dose of hepatitis B vaccine administered intradermally . J Med Virol 1984 ; 14 : 27 - 32 19. Redfield RR , lnnis BL , Scott RMc , Cannon HG , Bancroft WH. Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine . JAMA 1985 ; 254 : 3203 - 6 20, Centers for Disease Control, Immunization Practices Advisory Committee . Rabies prevention . MMWR 1984 ; 33 : 393 - 408 21, Bernard KW , Roberts MA , Summer J , et al. Human diploid cell rabies vaccine: effectiveness of immunization with small intradermal or subcutaneous doses . JAMA 1982 ; 247 : 1138 - 42 22. Osterholm MT , Garayalde SM. Clinical viral hepatitis B among Minnesota hospital personnel . JAMA 1985 ; 254 : 3207 - 12


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Stanely M. Lemon, Davis J. Weber. Immunogenicity of plasma-derived hepatitis B vaccine, Journal of General Internal Medicine, 2018, 199-201, DOI: 10.1007/BF02602339