Indian J. Pediat. 37 : 376, 1970

IMMUNOPROPHYLAXIS OF VIRAL INFECTIONS IN CHILDHOOD*

PEARAY L. OGRA**

Buffalo, New York

Civilized man discovered the con- Table 1. Mechanisms of defense cept of natural immunity long before against infection and bacteria were recognized as the causative agents of infectious diseases. It is particularly fascinating Non-specific to note that the development of many 1. Intact skin and mucous membrane viral and bacterial vaccines, and the 2. Lysozyme 3. Condition of growth : successful control of several infectious pH, oxygen tension, tempera ture diseases preceded the elucidation of the 4. Phagocytosis complex defense mechanisms of the 5. Complement host. Although Jenner discovered an 6. "Properidin system" and opsonins effective means of preventing Specific nearly two centuries ago, it is only 1. Delayed hypersensitivity in the past decade that the mecha- 2. Antibody : Serum nisms of induced immunity are being Secretory fully characterized and better under- stood. Before the specific aspects of immun- addition, lactic acid in the secretions zation against viral diseases is dis- of sweat glands, fatty acids in the cussed in greater detail, an attempt will sebum, and lysozyme play a role in be made to review briefly the defense preventing entry of infectious agents mechanisms which are normally present (Raffel 1961). prior to an infection, and those which As living organisms, viruses require develop in response to it. The impor- optimal conditions of temperature, pH, tant mechanisms of resistance to infec- and oxygenation, for replication in the tion are listed in Table 1. host tissue. Elevated body temperature, which often accompanies an inflamm- Non Specific Immune Mechanisms atory process has the ability to signifi- cantly dampen the multiplication of Intact skin and mucous membrane many viruses, and recovery is generally provides a mechanical barrier to the impaired when hypothermia is artifi- entry of the into the host. In cially induced. Acid metabolites, lowered pH, and lowered oxygen *From the Department of Pediatrics, School tension adversely affects the replica- of Medicine, State University of New York at Buffalo, and the Virology Laboratory, Children's tion of many viruses. Such factors Hospital, Buffalo, N. Y. seem to be beneficial to the host in **Postal address: Children's Hospital, 219 combating the infection (Baron 1964, Bryant Street, Buffalo, New York 14222, U.S.A. 1967). OGRA~IMMUNOPROPHYL~XIS OF VIR.AL INFECFIONS IN CHILDHOOD 377

Phagocytosis is an important defense immunized individual. Another pro- mechanism against many bacterial and tein constituent of normal human viral infections. Both circulating and serum which together with complement fixed phagocytes are in intimate con- and magnesium ions promotes phago- tact with a virus during viremia. eytosis and bacteriolysis, is termed The success or failure of certain viruses "properidin". Although the precise to multiply within phagocytes is well nature of properidin is a subject of correlated with the degree of virulence much controversy, it is generally (Bang and Warwick 1960). The thought to represent specific antibody, mechanism by which phagocytic cells perhaps resulting from stimuli of a recognize a substance as foreign is variety of antigens in nature. not fully understood. Among the Interferon is art important antiviral factors which enhance phagocytosis protein produced by virus-infected are the presence of surfaces against cells. It is a non-immunoglobulin which the cells can trap the antigen protein (molecular weight 20,000- particle for ingestion; e.g. surface 35,000). It is stable in a pH range phagocytosis for pneumococcus, highly from 2--11. Interferon is relatively polar surface with negative net electri- heat resistant, and non dialyzable. cal charge, particulate size of the anti- Although the precise mechanism of gen (0.02--5~ range), presence of speci- action is not fully understood, it is fic immunoglobulin, and complement. believed that establishment of ant iviral Complement is a series of non- action within cells requires RNA and immunoglobulin protein macromole- protein synthesis. Host cell-interferon cules, which are important to the interaction induces the formation of biologic effects of antigen-antibody new antiviral protein within the cell interactions. Alterations in the levels which appears to determine its eventual of serum complement have been antiviral activity. Interferon appears observed in a variety of diseases such to be species specific in action. as acute glomerulonephritis, rheumatic However, the antiviral effect seems to fever, rheumatoid arthritis, and in the be nonspecifie, i.e. Interferon produced development of cold agglutinins after to one virus is equally effective in certain viral infect!ons. However, the limiting replication of other unrelated function of complement in vivo is viruses (Glasgow 1965). still poorly defined. No definite relationship between the frequency of Specific Immune Mechanisms viral infections and the level of com- plement in the serum have been Delayed hypersensitivity. Intact demonstrated. mechanism of delayed hypersensitivity The opsonins represent a group of is an important aspect of immunity proteins or polypeptides, which have against many bacteria and certain the property of coating small antigenic viruses. The cell-bound element of particles, presumably altering surface immune response is exemplified by properties of antigens, and thereby, tuberculin sensitivity, and hypersensi- promoting phagocytosis arLd bacteri- tivity to drugs. This type of immune olysis. This property is normally response is mediated by sensitized associated with specific antibody in an lymphocytes. 378 INDIAN JOURNAL OF PEDIATRICS VOL. 37 NO. 271

Specifically sensitized lymphocytes blast transformation, and produce have the potential capacity of des- cylotoxic effects on target cells. troying virus infected cells in a manner Antibody. The antibody remains similar to homograft rejection. It is the principal, and often the single also possible that d:layed hypersensi- most effective means of protection tivity may inhibit virus replication by against . This specific promoting development of antibody immune response of the body, when containing exudate at the site of employed in the form of active immuni- initial virus multiplication. It is zation with viral vaccines or passive known that patients with impairment administration of immunoglobulin of cell mediated immunity, with or provides the effective image of natural without deficits in circulatory antibody, protection from infection with a are unusually susceptible to serious virulent virus. or fatal disease, particularly with The antibody activity is associated those viruses (smallpox, varicella, with a group of heterogeneous proteins, , etc.), in which induc- the immunoglobulins. The immuno- tion of delayed hypersensitivity may globulins are secreted by the lymphoid be the principal means of immunity ceils (plasma cells) of human lympho- against infection (Kempe 1960, O'Con- reticular tissues. Each immunoglobulin nell 1964). In general, however, molecule is composed of four polypep- infection with other commonly occurr- tide chains, a pair of light chains, ing viruses seem to have an apparent- Kappa (k) or Lambda i,X), and a ly normal course of recovery even in pair of heavy chains, which are the presence of defective delayed held together by disulfide link- hypersensitivity. Experimental studies ages. The immunoglobulins have have indicated that neonatal thymec- class specific determinants associated tomy, and subsequent absence of with their heavy chains. Based on delayed hypersensitivity, does not these antigenic differences, the immu- impair recovery, and transfer of noglobulins can be divided into five sensitized lymphocytes fails to induce major classes yG, ~,A, ~,M, ~,D, and recovery of mice from lymphocytic yE. Their physico-chem;cal charac- choriomeningitis virus infection (Vol- teristics are listed in q-able 2 (Ogra kert and Larson 1964). In clinical and Karzon 1970). situations patients with defective cellu- Owing to the specific properties of lar immunity do not seem to have an the heavy (v) chain, vG is the only increased susceptibility to infections immunoglobulin which is actively with most enteroviruses. transported across the placenta, and It is generally assumed that cell constitutes the sole source of protec- mediated element of immune response tive antibody in the newborn infant. is triggered by local interaction of Recently, it has been demonstrated antigen with specifically sensitized that the major classes of immunoglo- lymphocytes. This interaction is bulins present in the serum are also thought to induce the release of a detectable in varying amounts in variety of pharmalogic mediators different secretions bathing the muco- which inhibit macrophage migration, sal surfaces of the body. However, stimulate DNA synthesis to provoke the bulk of the immunoglobulin OGRA--IMMUNOPROPHYLAXIS OF VIRAL INFECTIONS IN CHILDHOOD 379

Table 2. Physico-chemical products of human immunoglobulins

Property 7G yA yM yD yE

i i i ii

Sedimet~tation coc~cient 7S 7S 19S 6S 8S

Molecular weight 160,000 (! 60,000) (900,000) 160,000 200.000

Electrophoretic mobility y Slow fl Between y Between y Fast y and ,8 and /3

Rate of synthesis 28 30 6.9 21 (mg/kg/day)

Half-life in serum (days) 23 6 5 2.8 2

total utilized per day 3 12 14 28

Normal adult level (mg[ml) 800-- 1500 60---490 37--210 0-- 30 Trace

~ data (From Ogra and Karzon. Ped. Clinics. N. diner. 17 : 385, 1970). in secretions is composed of a nnique various mucosal tissues (Crabbe and form of ~,A immunoglobulin. The Heremans 1967). On the other hand, secretory ~,A exists as a dimer of yM and yG producing plasma cells serum 7S~,A, to which is bound a predominate in systemic sites such as non-immunog/obulin protein unit spleen and lymph nodes. variously referred to as secretory piece, It appears that produetiort of secre- or Transport (T) piece. The "T" tory (IIS) type yA immunoglobulin piece usually exists as a portion of takes place locally in the mucosal the secretory 7A molecule, although interstitial plasma cells (Ogra et. al. in certain situations it may be 1968, Ogra 1969b). Convincing found free in the body fluids (Tomasi evidence has accumulated to suggest and Biencnstock 1968). The distri- that the efficacy of viral vaccines to bution of secretory ~,A, secretory prevent re-infection is largely dete:- piece, and other immunoglobulins mined by the optimal development in various body fluids is shown in serum as well as secretory antibody Table 3. responses (Ogra and Karzon 1969 a). Various studies employing fluores- Naturally acquired or vaccine induced cent labelled type specific antisera infections, such as poliomyelitis (Ogra to human immunoglobulins have et. al. 1968), (Bellanti et aL demonstrated immunologically com- 1969) (Ogra 1970) mumps, etc., petent plasma cells, producing pro- have shown to induce a serum as well dominantiy ./A immunoglobulin in as a secretory antibody response. 380 INDIAN JOURNAL OF PEDIATRICS TeL. 37 NO. 271

Table 3. Distribtaion of immunoglobul#rs in body fluids

Free Secretory Secretory Secretion ~,G ~M 7,D 7S vA 7,A I1S Piece

Parotid .. Tr Tr Tr - +

Tears .... Tr

Nasal .... Tr Tr Tr Tr +

Bronchial .... Tr Tr +

+ Colostrum .... Tr Wl" Tr Tr +

Gastric .... + i +

Intestine .... + + Tr + + I

Urine .... + + Tr + +

Sweat .... + + +

Uterine .... + Tr + +

Cervical .... + Tr + +

Seminal .... + + + +

CSF .... + Tr

Normal newborn .. + + +

Tr= trace + = present -- = absent BIank=iuadequate data

(From Ogra and Karzon. Ped. Clinir N. Am:'r. 17 : 385, 1970).

The immune response observed after response is elicited, the secretory anti- parental or oral immunization with body responses are conspicuously live atlenuated wiccines are in general absent. quite similar to those obmrved after However, if such inactivated viral naturally acquired infection. On the antigens are administered in high other hand, following parental immuni- doses locally in a mucosal surface, a zation with inactivated viral vaccine, secretory antibody response can be although appreciable serum antibody elicited, which may or may not be OGRA~ IIMMUNOPROPHYLAXIS OF VIRAl. INFECTIONS IN CHII.DllOOD 381 associated with a serum antibody res- Recent studies have demonstrated ponse (Ogra and Karzon 1969 a ). that the secretory antibody in naso- Secretory antibody response can be pharynx and alimentary tract affords expected after infection or immuniza- significant protection against re- tion with a replicating or non-replica- infection with a virus (Ogra and ting agent following local or parental Karzon 1969a). The degree of route of administration, when ade- resistance against re-infection ap- quate antigen mass is available to pears to be proportional to the level the mucosal immunocompetent tissues. of preexisting secretory antibody The use of inactivated vaccine depends as shown in the representa- mainly on the limited amount of tive model of poliovirus in antigen injected for stimulation. On Figure 1. the other hand, with live virus vac- At high levels of secretory antibody cines, a significantly larger antigen mass to poliovirus in the nasopharynx, is attained through self replication, replication of poliovirus in the nasopha- after the initiation of infection. rynx is almost completely blocked. Thus, it is not unexpected that live However, at lower levels of antibody, attenuated virus vaccine induces some replication of virus can go on a more effective response both in the ( Ogra and Karzon 1970 ). serum and secretions. The various There appears to be little doubt of modes by which mucosal immunity can the existence of a distinct m-chanism be manifested after immunization is of local immunity which functions schematically shown in Table 4. as the front line of protection at the

Table 4. Schematic representation of serutn anti secretory antibody response following immunization with a replicating or a non-replicating antigen.

Secretory Antib~dy Response

Immunized and Non-Immunized Tyr,r of Antigen Route of Serum Antibody Adjaccm Mucosal Distant Mucoml hnmunization Response Surface Surf,~cc

|

Replicating Local + ~- -- (live) Parentcral + +

Non-replicating Local -- + -- (inactivated) Parcnteral +

+ = present -- = absent

(From Ogra and Karzon. Ped. Clinics. NAmer. 17 : 385, 1970). 382 INDIAN JOt'RNAL OF PEDIATRICS VOL. 37 NO. 271

--- Ab (t I C~,-'",~' t: ,5 "~ 5 -

..J ~ , .i

a.

z z z ~, -., 0

u

1 8 24 40 S~ 72 POrtO VACCt~ :)AY ~, aF ttR Fts LIVs

fig I. i'ffccts of varying anaounts of pre-exi,~ting .r antib~-dy on tne replication of live poliovlrus.

mucosal sites, where primary replica- confer significant protection even in tion of virus takes place ( Tomasi the absence of any apprcciahle level 1967). From the clinical point of of serum antibody (Smith et al. 1966). view the significance of serum and On the oth~.r hand, the target organs secretory antibody will depend on involved in paralytic poliomyelitis are the natural pathogenesis and target those of the central nervous system. organs of virus infection. For It is known that paralytic disease example, the target organ in in- with wild poliovirus can be prevented fection with respiratory syncy- by serum antibody which has been tial virus, influenza virus, parainflu- induced by parenteral immunization enza virus, and rhinovirus is the wi,h inactivated (Salk p'alio vaccine). mucosa of the respiratory tract. In these In such a situation, the alimentary tract situations even substantial levels of does not contain specific secretory serum antibody may not afford pro- antibody, and reinfection of the tection against re-infection and sub- nasopharynx and alimentary tract with sequent clinical disease related to wild poliovirus can be induced at respiratory tract mucosa (Smithet al. a subsequent re-infection challenge 1967 ). However, specific secretory (Ogra et al. 1968 Ogra and Karzon antibody in the respiratory tract may 1969b). OGRAII.",tMUNOPROPIIYI.AXIS OF VIRAl. INFtTCTIONS IN CiilI.DIIOOD 383

Specific Viral Vaccines The duration anti efficacy of the response depends on the technique Smallpox of inlmunization, the ability of the In recent years, ~s a result of individual to produce specific anti- extensive control and eradication bodies, the potency of the vaccine lot programmes sponsored by various used, and the number of vaccnation national health agencies and the World scars. A high level of protection is Health Organization, the incidence conferred for at least a period of three of smallpox has sharply declined in years after immunization. Vaccina- many par.s of the world. Protection tion provides appreciable though of the general population agai~st declining immunity for 10-20 years smallpox, thr~)ugh of and may provide protection against a infants and rc-va~.cination of children fatal outcome for e~en longer periods. and adults, has been the most effec- Dixon has suggested that after single tive means of defense against the primary immuniza!ion, the chance ef spread of the disease. an attack of smallpox is reduced to 1 The degree cf resistance to small- to 1000 for one year, I to 200 for pox varies considerably in different threc years and I to 2 for 20 years individuals, particular',y in areas (a)ixon 1962). Following primary vacci- where significant reservoirs of endemic nation, hemagglutinating complement disease persist. It is apparent from lixing, and neutralizing antibodies the studies of Rao (1964) that are demonstrabl: in the serum after variation in the natural resistance to 8-12 days. infection in the absence of specific As a result, vaccination after expo- antibody may depend on the age sure to smallpox may not always ( discrete cases are most often seen in result in protection. the 5-14 year age group ), infecting Although c!rculating antibody pro- dose of the virus, physiologic activity vides a high degree of protection of the tissues, and other known non- against infection, sev=re complications specific factors, interferon, etc. of smallpox vaccination have been Permanent protection is the rule observed in patients with impaired following natural infection ( samllpox cell mediated immunity, even in the or alastrim ). Very rarely second presence of adequate circulating anti- attacks may occur. body levels. Smallpox vaccine. 'l'he bulk of vac- The natural portal of entry for the cine in use today is the "animal lymph,' virus is the upper respiratory tract. prepared essentially in a similar man- Virus is usually recovered from the ner as it was done 150 years ago, oropharynx from 6-10 days of illness. employing the skin of such suscep ible It seems reasonable to assume that animals as calf and sheep, for the secretory antibody response may be growth of virtJs. The effi- induced in the mucosal sites of repli- cacy of smallpox vaccine has never cation after natural infection. How- been measured precisely in controlled ever, no information is available on trials. However, it is generally agreed the appearance and persistence of that the vaccine is highly effec.ive in local antibody after natural or induced inducing a specifc immune response. infection with smallpox. 384 INDIAN JOUP.NAL OF PEDIATRICS VOL. 37 NO. 271

Vaccine Usage. Primary vaccina- et al. 1948). However, the efficacy tion may be performed at any age of this vaccine under heavy smallpox under conditions of exposure. Re- exposure has not been fully docu- vaccination should be performed on mented. entering kindergarten, and every three Vaccinia virus inactivated by form- years. The use of smallpox vaccina- alin or ultraviolet light has been shown tion is contraindica'ed in : (1) skin to induce circulating antibody res- disorders such as eczema or other ponse and modify the subsequent forms of dermatitis, in the individual primary take with animal lymph considered for wlccination, or in his live vaccine. However, protection household contacts. observed is of a lower order than (2) altered immune states, due to classic vaccination. Attempts have immunosuppressive therapy, (steroids been made to employ inactivated antimetabolites. X-rays, etc.), (3) vaccine as a priming antigen before dysgammaglobulinemia particularly in immunization with live virus in the those immunologic defects which are hope of reducing the complications of associated with impairment of cell live virus immunization (Beunders mediated immunity, e.g. thymic dys- et al. 1960). plasia, (4) malignancies of reticuloen- dothelial system, (5) leukemia, and Poliovirus (6) pregnancy (Committee on Infec- tious Diseases 1970). The inactivated poliovirus vaccine Vaccinia lnm~unoglobulin. Some of became available for commercial use the complications of vaccination can in 1955 and the live attenuated - be successfully prevented by the virus vaccine was licensed for general administration of gamma globulin use in 1961. A precipitous drop in prepared from hyper-immune volun- the incidence of paralytic pJliomyelitis teers. Vaccinia immunoglobulin has became obvious in the United States proved u~eful in modifying the course after the introduction of these vaccines. of such complications as eczema Approximately 90~ of the reduction vaccinatum and inoculation vaccinia. was attained after the use of inactiva- It has, however, little or no effect on ted vaccine alone (Chin et al. 1961). and po;t vaccinal lnactived (Salk) Vaccine. This vac- encephalopathy. Vaccinia immuno- cine is prepared by growing poliovirus globulin may also be used if vaccina- types in monkey kidney cell cultures tion is undertaken in the contra indi- and inactivating the infectivity of the rated situations listed above. virus by formalin treatment. The Other Vaccines. In addition to vaccine is generally used as a trivalent animal lymph, vaccinia virus has also mixture containing poliovirus types been grown in the ch.orioallantoic 1, 2, and 3. Although the use of membrane of chick embryos (Rivers inactivated virus (killed) vaccine has et al. 1939). Early experience with been almost completely replaced by this vaccine has indicated a lowered live virus vaccines in the United degree of immunogenicity. Large States, the killed vaccine is still widely scale field trials indicated almost 100% used in many parts of the world. take on primary immunization (Cook Earlier studies have clearly demon- OGRA--I.~I.~IUNOPROPHYLAXIS OF VIRAl. INFECTIONS IN CflILDIIO()D 385 stratcd that circulating antibody induc- into consideration in the etfizient use ed by parenteral immunization with of live poliovirus wtccincs. inactivated vaccine, although able to prevent viremia and spread to the Immunization ~ the Newborn. central nervous system, was incapable Newborn infants, in addition to of preventing nasopharyngeal or possessing transplacentally acquired alimentary infections. In recent studies maternal antibody, receive poliovirus it has been demonstrated that par- antibody in the maternal milk, parti- enterally administered inactivated cularly in areas where the principal vaccine fidis to induce a secretory means of infant feeding is maternal antibody response in the nasopharynx breast milk. Thus, the ability of the and alimentary tract (Ogra et aL 1968). newborn to acquire alimentary tract This would explain the susceptibility infection is sufficiently limited. In of alimentary tract to re-infection even order to:ninimize the neutralization of in the presence of appreciable levels vaczine virus by the secretory antibody, of circulating antibody. it has been suggested that breast feed- ing be withheld for a few hours Live Ata'nuated ( Sabin ) Vaccine. before and after the administration Live attenuated poliovirus is adminis- of vaccine (Katz and Plothin 1968). tered by mouth and initiates alimen- /lssociation of Paralytic Disease. tary infection in susceptible persons Association of paralytic disease and following immunization. The serum administration of poliovirus vaccine antibody response is essentially similar has been documented in several to the response obtained after paren- reports. However, in the majority of terai immtmization with killed virus reports, it has not been possible to vaccine (Salk). More significantly, prove that any individual case was however, following oral immunization caused by the vaccine. Unfortunately, wilh live (Sabin) vaccine, the secretory no h~boratory test is available to pro- antibody activity against poliovirus is vide a definitive answer. regularly seen in the nasopharynx Nevertheless, based upon epidemio- and alimentary tract (Ogra et aL 1968), log;cal evidence, it is suggested that a Thus, the principal advantages of number of cases compatible with immunization with live virus vaccine vaccine associa,ed paralysis is in the over inactivated vaccine are (1) the range of one case per four million capacity to inhibit the virus excretion doses of live poliovirus administered inthe immunized individual at a subse- (National Communicable Diseases quent exposure to wild virus, (2) the Centre 1968). immunization of non-immunized in- Interference. In areas where high dividuals through secondary spread of levels of infection with other entero- the attenuated virus, thus affording a viruses, such as echo, coxsackie, or more efficient herd immunity, (3) more adenoviruscs are pre~ent, a significant persistent antibody responses in the degree of interference with a success- immunized population, and (4) the ful alimentary infection with poliovirus ease of administration. has been frequently ob~rved (Feidman Despite theses obvious advantages, et al. 1964. The exact mechanism of tile following situation should be taken ~uch influence is not fully understood, 4 386 INDIAN JOURNAL OF PEDIATRICS VOL. 37 NO. 271

Such interference effects can be pre- Measles vented in most areas by administering vaccine during the season when the The incidence of complications which enteroviruses are not prevalent in may result after measles, makes this the community. However, in polio- disease one of the most important virus endemic areas, it is advisable to viral infections of childhood. Neuro. immunize, particularly the children, logic complications may occur in routinely, irrespective of the season. one of every 500 to 1000 cases (Tyler Vaccine Usage. When employing 1957). The incidence of bacterial trivalent live attenuated vaccine a complications is also significant, par- three-dose immunization schedule ticularly manifesting as otitis media should be started at two to three and involvement of the respiratory months of age in conjunction with tract. The highest case fatality rate is DPT. The second dose should be among children less than one year old given eight weeks later, the third (Karelitz et al. 1959). dose should be given eight to twelve Measles infection is a life threatening months after the second dose. When disease in children with leukemia, employing monovalent live vaccine, malnutrition, cystic fibrosis, immune- one dose of each of the three types logic deficiency and tuberculosis. It of live virus vaccine is given at six to is well known that after natural in- eight week intervals beginning at two fection with measles virus, and less to three months of age (Advisory frequently after immunization with Committee on Immunization 1969). live attenuated vaccine, the delayed A booster dose oftrivalant live vaccine hypersensitivity to tuberculin is is given eight to twelve months after temporarily suppressed. Such tuber- the third dose of monovalent vaccine. culin anergy in patients who were A certain number of failures of infec- previously tuberculin positive may tion which occur due to interference lead to massive dissemination of can possibly be overcome by such active tuberculin lesions, or reactiva- schedules of feeding. tion of clinically quiescent foci In areas where immunization with (Karzon and Henderson 1966). A com- live vaccine can not be undertaken, bination of malnutrition and under- immunization may be carried out lying tuberculosis may exp!ain the employing inactivated (Salk)polio high mortality rate in measles in the vaccine. Four doses of inactivated developing countries (Taneja et al. vaccine should be administered paren- 1962). terally, three at monthly intervals, and Live Attenuated Measles Virus the fourth dose six to twelve months Vaccine. The original Edmonston B after the third immunizing dose. This and the further attenuated strains of schedule can be combined with DPT Schwarz and Moraten are widely in beginning at one to two months of age. use. The vaccine is prepared in tissue In endemic areas a booster dose of in- culture using chick embryos or dog activated vaccine is recommended every kidney for the growth and attenua- throe to four years to insure adequate tion of the virus. Parenteral adminis, levels of serum antibody (Advisory tration of attenuated virus vaccine Committee on Immunization 1969). re,suits in mild measles infection. The OGRA~IMMUNOPROPHYLAXIS OF VIRAL INFEC"rlONS IN CHILDHOOD 387

vaccine induced measles differs from immunization the fever rarely exc,ee.d~ natural infection in having a shorter 101 ~ and the frequency of rash is , the rash and fever reduced by approximately 25 to 50%, is significantly modified, and the com- Although all children who are given plications are virtually eliminated. measles immunoglobulin at the time Further, the attenuated vaccine strains, of immunization respond with serum although replicating in the systemic antibody production, the responses lymphoid tissue usually can not be are generally lower than those who recovered from the blood stream or are immunized with live attenuated the respiratory tract. Susceptible vaccine alone. It has also been sug- children in intimate contact with gested that the duration of antibody immunized persons remain free of persistence may be somewhat lower infection. Following immunization, ( Weibel et al. 1964 ). the antibody is demonstrable in the If measles immune globulin is used serum in two weeks and persists in in conjunction in with live virus vaccine, appreciable titres for several years. the vaccine should be injected in Vaccinees who have appreciable anti- another arm to permit adequate body levels in serum have been found attachment and penetration of live to be fully protected against natural virus in susceptible cells. disease. Recently, clinical break- Inactivated Vaccine. The inactiva- throughs have been observed in several ted (killed) measles virus vaccine is immunized population groups. Such prepared from Edmonston's strain instances seem to be due to an initial grown in primary monkey kidney or vaccine failure and absence of serum chick embryo cell cultures, and inacti- antibody response (Lerman and Gold vated with formalin. The vaccine is 1970). partly purified by precipitation on Although live virus induced alum. Following parenteral immuni- immunity provides protection against zation with inactivated vaccine, the clinical disease, the respiratory tract antibody titres in serum, although in many vaceinees may still be suscep- appreciable, are generally lower than tible to re-infection. Recent studies those observed after natural infec- have suggested that parenteral adminis- tion or immunization with live virus tration of live virus vaccine may not (Karzon and Henderson 1966), Most always induce secretory antibody res- significantly, however, the antibody ponse in the nasopharynx and lower declines more rapidly, and is undetee- respiratory tract, which is the natural table after one year. The serum portal of entry for live virus antibody response elicited after ( Ogra 1970). Absence of local secre- inactivated virus appears to be tory antibody in such individuals may less efficient than antibody response explain the apparent susceptibility to after natural or induced infection in re-infection. preventing subsequent infection. The reactions to immunization Recent studies have demonstrated with live attenuated virus can be that although parenteral immunization further diminished by simultaneous with live vaccine generally induces a administration of measles immune local secretory antibody response in globulin. Under such a practice of the respiratory tract ; however, ~8 INDIAN JOURNAL OF PEDIATRICS VOL. 37 NO. 271 following parental immunization with exposure ( Advisory Committee on inactivated vaccine, such secretory Immunization 1969 ). antibody response is conspicuously absent (Bellanti et al. 1969 ). Mumps Despite the rapid disappearance of antibody from serum, immunization Mumps is one of the commonest of with inactivated virus is often accom- viral diseases occurring in greatest panied by a hyperreactive state for a frequency in school age children. prolonged period, which results in a However, 15 to 20 7o of cases booster type of response at a subse- occur after the onset of puberty. quent re-infection with live or killed Serious complications are rare in virus. pre-pubertal illness, although aseptic Vaccine Usage. Inactivated vaccine meningitis, meningocephalitis, nerve i's generally not recommended for deafness can occur rarely. On the routine immunization. This is because other hand, in post-pubertal illness, of its poor immunogenicity and the extremely painful complications some of the serious side effects en- of orchitis is reported in 20 to 30% of countered after cxposure to natural males ( Harris et al. 1968 ). However, disease (discussed later in lhe section sterility is rare. All naturally occur- on immunologic balance ). ring mumps confers long lasting The live attenuated virus vaccine immunity against re-infection. Second is recommended for general use in all attacks are rarely reported. Approx- Susceptible children. It is most useful to imately 309/o of natural infection are vaccinate susceptible children entering subclinical. ~nursery schoool and kindergarten, Live Mumps Virus Vaccine. This preferably at about one year of age. vaccine is prepared in chick embryo Edmonston B strain may be accom- cell culture. Following immunization :panicd by administration of measles with attenuated mumps virus vaccine, immune globulin. Immunoglobulin 78% of children have responded should not be given with further with the development of appreciable attenuated vaccine. Live attenuated antibody titre. The titres are generally vaccine can usually prevent disease lower than those induced by natural if given before or on the day of disease. The antibody levels have exposure to natural disease. Live remained elevated at least four years virus should not be given to patients after immunization. Protection against :with tuberculosis unless they are infection appears to be 1007o. actively under treatment. The use of live Unlike , mumps vaccine is con~ra-indicated in altered virus vaccine does not cause local or immune states, immuno-suppressive general reaction. therapy, dysgammaglobulinemia, leu- Vaccine Usage. Mumps virus vaccine kemia, and other generalized maligno- may be used at any age. However, it sis. In such. situations, one may is advisable not to use the vaccine in attempt immunization with inactivated children under 12 months of age. The measles vaccine or passive immuniza- vaccine may be particularly considered tion with measles immune globulin in children approaching puberty, and ,as soon as possible after known adults, particularly male, who have OGRAmIMMUNOPROPHYLAXIS OF VIRAL INFECTIONS IN CHILDHOOD 389 not had clinical mumps parotitis. It immunity in the population, may is not known whether live attenuated undergo spontaneous rearrangement, muml~ virus vaccine provides protec- resulting in a variant form which tion if it is administered after exposure replaces the previously dominant to natural disease. However, there is strain. This variant has the potential no contra-indication to such a use. for spread and production of disease, Until further data are available, it is provided it is sufficiently distinct suggested that immunization with live from the previous strain to evade the mumps virus vaccine should not bo heterologous serum antibody (Zhdanov performcd in severe febrile illnesses, 1962). hypersensitivity, and altered immune Thus, the development of an effec- states, and immunologic deficiency tive vaccine has been complicated by diseases (Advisory Committee on the problem of multiple antigenic Immunization 1969). variants and complex antibody res- ponses. Because of these complica- Influenza ting factors, the quality and duration of immunity to influenza virus has Influenza is world wide in distribu- not been adequately determined, tion. Over the years epidemics have Influenza Virus Vaccines. Whenever appeared in different parts of the world nation-wide epidemics or infection in with a striking periodicity. Outbreaks a large segment of population is antici- are most common in the period from pated, it is necessary to revise the exis- early autumn to late spring. In any ting influenza vaccine formulation in epidemic area the peak of infectious .order to include contemporary dominant cases is reached in three weeks and the antigens. The standard influenza virus course is generally completed in another vaccine is a trivalent inactivated pre- three to four weeks. Influenza infec- paration containing all three types of tions are characterized by high mor- viruswhich is administered parenter- bidity and low mortality. Mortality ally. is particularly high in the elderly and Following subcutaneous administra- the debilitated. tion of the inactivated vaccine, appre- There are three major types of in- ciable serum antibody response is fluenza virus, A, B and C. Epidemics .demonstrable in eight to ten days. of one or the other type have plagued The antibody levels then decline and various parts of the world repeatedly. may be undetectable after a year, Epidemics with the same virus type Most significantly, immunization with seem to re-occur after an interval of inactivated vaccine by a parenteral eight to ten years. Available evidence route generally fails to induce secretory suggests that in a period of ten to antibody response in the nasopharynx twelve years, a given family creates and respiratory tract. As mentioned such widespread immunity as to limit previously, the target organs of the the spread of that particular virus disease after infection with influenza type. It is well known that influenza virus is the mucosa of the respiratory virus is highly mutable. Each virus tract. In view of the suggested protec- type is comprised of a finite number tive role of secretory antibody, it is of antigens which under the stress of reasonable to conclude that circulating 390 INDIAN JOURNAL OF PEDIATRICS VOL. 37 No. 27I

antibody in the absence of secretory infection during early pregnancy. The antibody may afford little or no pro- intra-uterine rubella infection is cha- teetion against clinical disease. This racterized by typical anomalies of would explain lhe relative inefficiency deafness, congenital heart disease, of the existing inactivated vaccine. cataracts, microcephaly, and mental Recent investigations have been direc- retardation. ted towards development of secretory This clinical picture is collectively antibody in the respiratory mucosa by referred to as the congenital rubella local intranasal immunization with live syndrome (Cooper and Krugman 1967). influenza virus or inactivated influenza The mechanisms responsible for the virus vaccine. Enormous experimental teratogenicity of rubella infection in evidence has accumulated in the past utero are not known. Recent studies decade which suggest that locally in- have suggested that rubella infection duced antibody to influenza virus may inhibits mitotic processes in cell be a better index of resistance against division and increases the number of disease than the circulating antibody. chromosomal breaks (Plotkin et al. Immunization by a local route seems 1965). It would seemthata dissemina- to hold a significant promise of effec- ted infection of the fetus during the tive local protection against the period of organogenesis (first trime- disease (Waldman et al. 1969). ster ) would interfere with normal Vaccine Usage. Until appreciable evolution of the organs, thus resulting protection is provided consistently by in various forms of malformation. the influenza virus vaccines, it is not Following intra-uterine infection, recommended for routine immuniza- 75~ of women may abort spontan- tion of healthy adults and children eously. If infection is acquired in (Advisory Committee on Immunization the first trimester of pregnancy, in- 1969). Despite its limited effec- cidence of the congenital rubella tiveness, the vaccine should be con- syndrome in the newborn may be as sidered for poor risk patients, par- high as 80 to 90 ~o. ticularly for chronically debilitated Live Attenuated Vac- conditions, chronic bronchopulmonary cine. The most effective means of disease, old people with arteriosclero- preventing rubella infection during tic complications, etc. The immuniza- pregnancy and subsequent birth of tion should be carried out in a series babies with the rubella syndrome of two doses administered subcu- would be the widespread use of a safe taneously six to eight weeks apart. and effective live virus vaccine. It is hoped that immunization with such Rubella a vaccine will eliminate the transmis- sion of virus among children who are Rubella is the mildest of the viral the major source of infection for suscep- infections of childhood. Uneventful tible pregnant women. recovery is the rule in childhood in- Recently, live attenuated rubella has fections. However, rubella is a disease been licensed in the United States of major importance because of high and in several Western European incidence of congenital defects in countries. Attenuated rubella virus newborn infants whose mothers acquire vaccine is prepared by propagation of OGRA~IMMUNOPROPHYLAXIS OF VIRAL INFECTIONS IN CtlILDHOOD 391 rubella virus strains indog kidney, duck carried out in the laboratory of th~ embryo, African green monkey kidney, author indicate that although naturally or rabbit kidney tissuse cultures. The acquired rubella virus infection is al- two commercially available vaccines ways accompanied by appearance of are HPV-77 prepared in duck embryo secretory antibody in the nasopharynx, or dog kidney and Cendehill-51 pre- such response is seen only occasionally pared in rabbit kidney. following parenteral immunization Following immunization with atte- with live attenuated rubella virus nuated rubella virus, appreciable vaccine. serum antibody levels are demonstra- Vaccine Usage. Live rubella virus ble in seven to ten days. The anti- vaccine is recommended for boys and body response is generally lower than girls in the pre-pubertal age. Vaccine the response observed after natural is not recommended for infants less infection. Serum antibody levels have than one year of age. Vaccination decreased only slightly during three of adolescent or adult males is of years of observation. Although long much lower importance because sa term protection is likely, its exact few are susceptible. It is not yel duration is yet to be determined. determined as to what extent infection Following parental administration of of the fetus with attenuated virus may vaccine, transient pharyngeal shedding take place. Therefore, immunization of virus has been observed. It is of susceptible adolescent or adult estimated that 30 to 50~ of children females should be c:trried out onty immunized in such a way may excrete after pregnancy is ruled out and conceit, virus in the nasopharynx for two to tion can be effectively prevented three weeks after immunization during the next two months after ( Dudgeon et al. 1969 ). However, immunization. thereis no evidence of communicability Immunization of suscep:ible preg- for the shed vaccine virus. Recent nant women is contraindicated until investigations have shown that immuni- more more information is available zation affords protection against illness ( Advisory Committee on lmmuniz~t- following either natural exposures or tion 1969 ). artificial challenge. It may, however, be pointed out Concepts of Immunologic Balance in that following such reinfection chal- Immunization lenge by the oral pharyngeal route, in approximately 50-70~ of immunized Recently, it has been observed that children, replication of virus in the children previously immunized with nasopharynx can be frequently demon- parenterally administered inactivated strated (Hoitmann et al. 1970. The measles virus vaccine when re-immu- apparent susceptibility of the respira- nized with live attenuated measle~t tory tract to infection in children vaccine develop atypical skirt rest, immunized with parenterally adminis- ti.ons at the site of immunizatioJ~, tered vaccine appears to be related manifest a generalized, somotime~ to poor secretory antibody responses fatal, vasculitis, when exposed to following such a route of immunization natural measles infection 1. Scott and (Ogra 1970). Preliminary investigations Bonanllo 1967). This phenomemoat 392 INDIAN JOURNAL OF PEDIATRICS VOL. 37 NO. 271 appears to represent an abnormality tially responsible for such reactions, of the immune response which results since such deposits are generally not from an inappropriate immunologic found in the local sites of delayed stimulus relative to the immunologic hypersensitivity (Bellanti et al. 1969 ). response. Similar mechanisms seem A similar immunologic difficulty has to exist in fulminating sepsis, or during been observed in infections with immunization with live vaccine in respiratory syncytial virus. immunologic deficiency diseases, such This virus is the commonest etio- as the development o(vaccinia gan- logic agent of bronchiolitis in infants. grenosa after smallpox immunization, During experimental trials of paren- in patients with impaired cellular teral immunization with inactivated immunity. Immunologic imbalance respiratory syncytial virus vaccine, it may also be encountered when cell was observed that such immunized production of immune response may infants developed a most serious and be inappropriate to the stimulus, often fatal form of bronchiolitis when such as occurs with increased ~,E exposed to natural infection (Chanock immunoglobulin production in atopy. etal. 1968). This paradoxical situa- In the preceding section, it has been tion seems to be partly explained by suggested, that in general, immuniza- a similar mechanism which operates tion with inactivated vaccine adminis- in the pathogenesis of atypical reac- tered by a parenteral route selec- tions to inactivated measles virus tively stimulates the humoral anti- vaccine. Following natural infection body response with a conspicuous with respiratory syncytial virus, an lack of secretory antibody response. immediate recall of serum antibody Such antibody responses may repre- was speculated which would complex sent yet another form of immunologic with virus within the respiratory tract imbalance. The atypical reactions leading to immunologic injury to the seen after immunization with inacti- respiratory mucosa. vated measles vaccine appear to be Another form of inappropriate mediated by hypersensitivity (Bellanti immunologic balance may exist in et al. 1970). It is not certain whether development of paralytic poliomyelitis the manifestations are those of in children whose tonsils have been immediate or delayed hypersensitivity. previously removed. It is known One of the most striking features in that recent or remote removal of these children is the absence of circu- tonsils and adenoids significantly lating antibody. Vasculitis induced increases the risk of spinal or bulbar by immunologic mechanisms is charac- poliomyelitis during epidemics of terized by the disposition of immune poliovirus infection. The mechanism complexes in the affected tissues. by which tonsillectomy modifies the Complexes of ~,G immunogiobulin- pathogenesis of poliovirus infection measles virus-complement (C'3) have is not known, although trauma asso- been observed in the atypical skin ciated with the tonsillectomy during reactions of measles. On the basis of invasive stage of the disease has been these observations it has been sugges- thought to be an important predispo- ted that immediate hypersensitivity sing factor. (arthus type of reaction) may be par- Recent studies have demonstrated 0GRA~IMMUNOPROPHYLAXIS OF VIRAL INFECTIONS IN CHILDHOOD 393 that complete removal of tonsils and altered immunity and hypersensitivity. adenoids in children immunized with Further, the success which has been live poliovaccine may deprive such attained with the use of live attenua- children of a significant source of ted vaccine, suggests that the immunocompetent tissue in the naso- development of local immunity at the pharynx, which may be actively primary portal of entry may eventually involved in the replication of polio- provide an effective means of eradi- virus, and the synthesis of specific cation of pathogenic virus flora in antibody. In view of the suggested any community. protective role of secretory antibody in the nasopharynx, it appears that References deficiency of local antibody as a result of tonsillectomy may permit Advisory Committeeon Immunization. (1969). more extensive virus replication in the In Morbidity and Mortality. Weekly Reports of Communicable Diseases Centre, Atlanta, Ga. nasopharynx, and thus, increase the 18, 43. risk of direct involvement of the Bang, F.B. and Warwick, A. (1960). Proc. central nervous system after an infec- Natn. Acad. Sci. 46, 1065. tion with wild poliovirus (Ogra Baron, S. (1964). Adv. Virus Res. 10, 39. 1970 b). ldem. (1967). Modem Trends in Medical Virology. Appleton Century Crofts, New York. Bellanti, J. A. et al. (1969). New Engl. J. Conclusion Med. 280, 628. Idem.(1970). In Conference in Secretory It appears that an ideal vaccine would Immunologic System. Veto Beach, Florida, be the one which closely simulates 10-13December 1969. In press. Beunders, B. J. W. et al. (1960). Arch. ges. the immunologic events occurring Virusforsch. 10, 382. during the course of natural infection. Chanock, R. M. etai. (1968). In Perspec- Natural infection through the natural tives in Virology. Ed. M. Pollard. Volume VI. portal of entry seems to induce serum Chin, T. D. Y'. et al. (1961). Amer. J. Hyg. as well as secretory antibody response. 74, 67. Committee on Infectious Diseases. (1970). Live attenuated vaccine administered Annual Report. 16th Edition. American Academy orally most closely resembles natural of Pediatrics, Evanston, III. infection in eliciting a balanced O'Connell, C. et al. (1964). Ann Intern. Med. immunologic response. However, 60, 282. parenteral immunization with inacti- Cook, E. B. M. et al. (1948). Pub. Hlth. Rep. 6, 50. vated vaccine may be complicated by Cooper, L. Z. and Krugman, S. (1967). Arch. unbalanced immune response stimula- Ophthal. 71,434. ting the humoral system without any Crabbe, P. A. and Heremans, J. F. (1967). secretory antibody production. Lab Invest. 16, 112. Current approaches in immunopro- Dixon, C.W. et al. (1962). Brit. med. J. I, 1262. phylaxis of viral disease are thus Dudgeon, J. A. et al. (1969). Ibid. 1,271. directed at immune mechanisms which Feldman, R. A. et al. (1964). Pediatrics, 33, lead to uniform stimulation of only 526. certain components of the immune Glasgow, L. A. (1965). 3. Pedlar. 67, 104. system. Hopefully, this approach Harris, R. W. et aL (1968). Amer. J. Epide- miol. 88, 224. would lead to balanced immunologic Horstmann, D. M. et al. (1970). Abstracts of responses rather than a situation of American Pediatric Society Annual Meeting. p. 4. 394 INDIAN JOURNAL OF PEDIATRICS VOL. 37 NO. 271

Karzon, D. T. and Henderson, D.A. (1966). Raffel, S. (1961). Immunity, Appleton. Adv. Pediat. 14, 121. Century-Crofts, New York, p. 3. Karelitz, S. et al. (1959). J. Pediat. 54, 1. Rao, A. R. (1964). J. Indian reed. Assoc. 43, Katz, M. and Plotkin, S. (1968). J. Pediat. 224. 73, 267. Rivers, T. M. et al. (1949). J. exper. Med. Kempe, C. H. (1960). Pediatrics, 26, 176. 69, 857. Krugman, S. et al. (1968). Amer. J. Pub. Hlth. Scott, T.F.M. and Bonanno, D.E. (1967). 52, Suppl. 16. New Eng. J. Med. 2/7, 243. Lerman, S. J. and Gold, Eli. 0970). Society Smith, C. B. et al. (1966). New Eng. J. Med. for Pediatric Reserch. Annual Meeting, Abstracts. 275, 1145. p. 65. Smith, C. B. et al. (1967). J. Immunol. 99, 133. National Communicable Diseases Centre. Taneja, P. 1'4. et al. (1962). Amer. J. Dis. (1968). Annual Poliomyelitis Summary. Child. 103, 226. Ogra, P. L. (1970). Unpublished data. Tomasi, T. B. (1967). Hosp. Pract. 7, 26. Ogra, P. L. (1970). American Pediatric Tomsi, T. B. and Bienenstock, J. (1968). J. Society. Annual meeting abstracts, p. 1. Adv. lmmunol. 9, 1. Ogra, P. L. et al. (1968). New Eng. J. Med. Tyler, H. R. 0957). Medicine, 36, 147. 279, 893. Volkert, M. and Larsen, J. H. (1964). Acta Ogra, P.L. and Karzon, D.T. (1969). J. Path. Microbiol. Stand. 60, 577. Immunol. 102, 15. Waldman, R. H. et al. (1969). In Conference Ogra, P. L. and Karzon, D.T. (1969). J. on Secretary Immunologic System, December lmmunol. 102, 1423. 10-13, 1969, Vero Beach, Florida, In press. Ogra, P. L. alad Karzon, D.T. (1970). Ped. Weibet, R.E. et al. (1964). New England Clin. N. Amer. 17, 385. J. Med. 270, 172. Plotkin, S.A. et al. (1965). Amer. J. Zhdanov, V. M. (1962). J. Hyg. Epidem. 6, Epiderniol. 81, 71. 142.