Vaccines in Pregnancy

VACCINE RECOMMENDATIONS: CHALLENGES AND CONTROVERSIES 0891-5520/01 $15.00 + .OO

VACCINES IN PREGNANCY

Flor M. Munoz, MD, and Janet A. Englund, MD

Neonates and young infants are susceptible to significant morbidity and mortality caused by bacterial and viral pathogens. Maternal antibodies transmitted transplacentally before birth confer protection against viral and bacterial diseases that are often serious in the first months of

28, 65, 66 In general, active immunization has not been successful in this age group beqause of the immaturity of the immune response, the length of time required to develop protective immunity, and interference of maternally derived antibodies. Furthermore, the safety of administer- ing vaccines in young infants remains a concern and requires careful evaluation. New technological advances in the development of safer and effective vaccines, along with information collected in recently conducted studies, make maternal immunization a plausible option for the prevention of life-threatening diseases in this vulnerable population.21, 53

CONCEPT OF MATERNAL IMMUNIZATION

The goal of maternal immunization is to endow the neonate and the infant with sufficient concentrations of pathogen-specific antibodies to resist infections during a period of vulnerability. During pregnancy, women are capable of mounting an adequate humoral immune response to vaccines. Maternal immunoglobulin (IgG) antibodies, preferentially of the IgGl subclass, are transported actively to the fetus throughout ge~tat ion.~~ Transplacenta1 passage increases substantially in the last 4 to

From the Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas (FMM), and Section of Infectious Diseases, University of Chicago, Chicago, Illinois UAE)

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

VOLUME 15 - NUMBER 1 * MARCH 2001 253

254 MUNOZ & ENGLUND

6 weeks of gestation with the enlargement of the pla~enta.2~ Concentra- tions of antibody, particularly IgGl subclass, can be higher in term newborns than in the mother.19, 20, 46 Maternal IgG has a half-life of 3 to 4 weeks in the newborn, waning during the first 6 months of life.69 The duration of protection correlates with the level of antibodies present at birth. Infants born with high antibody concentrations resulting from active immunization of their mothers could be protected for the time required for their immune system to respond adequately to vaccines. Premature infants would be unlikely to benefit from maternal immunization because of decreased antibody transfer before the third trimester of gestation.

Benefits of immunization during pregnancy include the potential to interrupt the transmission of certain pathogens from mother to infant at the time of birth (e.g., human immunodeficiency virus [HIV], herpes simplex virus [HSV], group B streptococci [GBS]); to delay the administration of vaccines in the first 6 months of life (e.g., respiratory syncytial virus [RSV], parainfluenza, pneumococcus, Huemophilus ivlfluenzae type b [Hib]); and to obviate the need for immunization against pathogens that cause severe disease ohly in the neonatal period (e.g., GBS).

PAST EXPERIENCE AND SAFETY

Vaccination of pregnant women has been practiced extensively in the United States since 1957. The first vaccines that were recommended and administered routinely during pregnancy in the United States from 1957 through 1966 were the influenza and poliovirus vaccines. In one study from that era, over 50,000 women were followed during pregnancy and delivery. All exposures during pregnancy, including vaccines, were recorded, and for 7 years the children were examined intensively for malformations, learning disabilities, hearing impairment, and development of malignancy. Immunizations during pregnancy were frequent and included inactivated polio vaccine (IPV), live attenuated oral polio vaccine (OPV), inactivated influenza vaccine, tetanus, and diphtheria toxoid vaccines. Immunization of women during pregnancy was not associated with adverse outcomes or an increased risk for any disability in the infants in this study.35

The safety and efficacy of maternal immunization for the prevention of infectious diseases in infants have been documented repeatedly and proven with the success of tetanus toxoid vaccination during pregnancy, now carried out world~ide.2~ Tetanus toxoid given to pregnant women is safe and has reduced dramatically the incidence of neonatal tetanus in many regions of the world.

Pregnancy has been considered a contraindication to vaccination with live virus vaccines because of the theoretical risk that live vaccine viruses could cross the placenta and infect the fetus. Current guidelines state that reasonable precautions should be taken to prevent their administration during pregnancy. Inadvertent vaccination of a pregnant

VACCINES IN PREGNANCY 255

woman with live virus vaccines should not be considered a reason to recommend interruption of pregnancy, however. As an example, data collected before 1979 on 538 women vaccinated during pregnancy with rubella vaccines failed to show cases of congenital rubella syndrome. The effects of the RA 27/3 strain live-virus rubella vaccine, licensed in 1979 in the United States, in 683 women who received it within 3 months before or after conception, were closely followed by the Centers for Disease Control and Prevention (CDC) from 1979 through 1988; no evidence was found that the vaccine caused any fetal abnormalities or congenital rubella syndrome.17 Furthermore, live attenuated polio vaccine has been well tolerated by pregnant women.18, 49

CONCERNS AND CONTROVERSIES OF MATERNAL IMMUNIZATION

Barriers to the widespread implementation of maternal immunization as a public health strategy to prevent infant disease in the United States and other industrialized countries stem from theoretic concerns about the safety and implications of this intervention, the relatively limited knowledge in the field, and practical socioeconomic and cultural issues. The most important concern with the use of vaccines during pregnancy is the safety of the fetus and newborn, although to date, no untoward effects have been documented for any vaccine. In general, maternal immunization with any vaccine is preferable during the later stages of pregnancy, when the fetus is fully developed, to avoid any potential interference with normal fetal growth and development. Live virus vaccines currently are avoided during pregnancy to prevent the potential risk of infection to the fetus and related congenital anomalies. When live virus vaccines (eg., rubella, varicella, OPV) have been administered to pregnant women, however, there has not been an increase in the occurrence of adverse events in the fetus and newborn. Some of these vaccines are indicated in pregnant women at high risk of exposure (e.g., OPV, yellow fever). This theoretic risk is diminished further by the use of newer vaccines derived from specific and highly purified viral or bacterial antigenic components (e.g., RSV, parainfluenza).

Potential risks to the mother include reactions to the vaccine, particularly anaphylactic responses that could compromise the course of the normal gestation, such as induction of premature labor. Such events have not been observed in studies of women immunized in the third trimester of pregnancy, however. When present, vaccine reactions usu- ally have been limited to local reactions at the site of immunization, that can be milder in pregnant women than in the general population.20

Another theoretic risk is that of inhibition or alteration of the infant's subsequent responses to natural infection or immunization by passively acquired antibodies to the vaccine antigen or carrier protein. One hy- pothesis is that transplacental passage of these anti-idiotypic antibodies could result in priming of the infant's immune system and activation

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or enhancement of the infant’s immune response. This has not been documented with the administration of immunoglobulin or monoclonal antibody products to pregnant women or however, and immunization with bacterial vaccines (e.g./ meningococcal polysaccharide vaccine [serogroup A and C],”’ tetanus toxoid, and Hib vaccine) during pregnancy have not resulted in interference of serocon- version after active immunization in young infantsz1, 22, 53, 55 (Fig. 1). Furthermore, infants with lower antibody concentrations after initial immunization respond adequately to booster doses of vaccine and achieve protective concentrations of antibody on completing the primary series of immunizations (e.g./ Hib, hepatitis A). More information should become available as more studies are completed, such as a current study that evaluates immunization of infants with pneumococcal conjugate vaccine after maternal immunization with pneumococcal polysaccharide vaccine.

The beneficial effect of decreasing maternal carriage of pathogens that are transmitted vertically to the infant at birth (e.g., GBS, HSV, HN) could be significant, Fepresenting a desirable advantage of maternal immunization. Determining this effect, however, would require long- term close follow-up of a large population. The effects of carriage of potential pathogens by children of immunized mothers are less obvious. Infants immunized with Hib, pneumococcal, or meningococcal polysac-

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First Dose Last Dose Figure 1. Proportion of infants born to mothers immunized with H. infiuenzae type B (HiB) vaccine (solid bar) or to controls (hatched bar), who had anti-PRP antibodies 20.15 &g/ mL after the first and last doses of routine Hi6 immunization given at 2, 4, 6 and 15 months of age. Mothers and infants received either HiB polysaccharide or conjugate vaccine. Infants born to mothers immunized with HiB vaccine had higher levels of anti-PRP antibody after the first dose of immunization than controls (P = ,00002). After the last dose, 100% of infants in both groups had antibody levels of PRP considered to be protective for disease. Data from Englund JA, Glezen WP, Piedra PA: Maternal immunization against viral disease. Vaccine 16:1456-1463, 1998; and Mulholland K, Suara R, Siber G, et at: Maternal immunization with Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine in The Gambia. JAMA 275:1182-1188, 1996.


Pneumococcus Vaccine

Control

Figure 2. Proportion of positive nasal wash cultures for pneumococcus in infants born to women immunized with pheumococcal polysaccharide vaccine in the third trimester of pregnancy (solid bar, n = 31) vs. controls (hatched bar, n = 63). A tendency toward decreased nasal carriage of pnemococcus was observed in infants of vaccine recipients (P = ,078). Data from Englund JA, Glezen WP, Thompson C, et al: Haemophilus influenzae type b-specific antibody in infants after maternal immunization. Pediatr infect Dis J 16:1122- 1130, 1997.

charide vaccines exhibit transient decreases of nasal colonization rates of these pathogens.23 Infants of mothers immunized with pneumococcal polysaccharide vaccine also have delayed nasal colonization of vaccine specific serotypes (Fig. 2). These effects indicate local protection in infants and mothers; however, the mechanisms mediating these effects and their consequences require further study.

Immunization of mothers during pregnancy has the potential to increase pathogen-specific antibody concentrations in breast milk and colostrum that would be transmitted to breast-fed infants. Although the production of specific antibodies in breast milk has been documented in only a few studies, there is evidence that antibodies, particularly IgA, are present in higher concentrations in women immunized with Hib or pneumococcal polysaccharide vaccines during pregnancy than in contr01s.~~ The effects of these antibodies in the infants are less well understood.

As a public health strategy, immunization during pregnancy repre- sents a valuable opportunity to prevent infant disease in some high-risk women who might not seek medical care except during pregnancy. It is also an opportunity to decrease substantial morbidity and mortality from illnesses that currently are not preventable by other means. To be successful, the impact and consequences of target diseases need to be recognized by obstetricians and the general public, and accessibility to immunization of high-risk populations needs to be assured. Health education is therefore essential, particularly in areas where other potentially constricting socioeconomic and cultural factors are in place. In a litigious environment for vaccine manufacturers and medical prac-

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titioners, the success of maternal immunization programs depends on studies that produce strong and consistent data demonstrating the safety and efficacy of vaccines, and on the acceptance of this strategy by scientific and general communities.

SPECIAL CONSIDERATIONS IN THE DEVELOPMENT OF VACCINES FOR USE DURING PREGNANCY

Candidate vaccines for maternal immunization should be minimally reactogenic to avoid any maternal reactions that could complicate pregnancy and labor. They should be safe for both mother and fetus, and therefore adequate for administration in the later part of gestation. This would minimize the possibility of infection and potential adverse events affecting the fetus. The concern that maternal vaccines could affect fetal development is reduced substantially with administration during the last trimester of gestation. Optimally, vaccines for maternal immunization should elicit high IgGl responses in the mother, substantial enough to cross the placenta effectively and achieve high levels in the neonate. To achieve the maximum amount of antibody production and transmission to the fetus, the interval between maternal immunization and delivery should be greater than 2 weeks. Ideally, vaccine components should be specific or highly purified antigens rather than whole cell bacteria or live viruses, and they shouId be sufficiently immunogenic to require no more than a single dose during pregnancy, to ensure compliance and acceptability as a public health strategy. Ideally, vaccines should not require repeated administration during subsequent pregnancies.

Several methods are currently available to develop safe and immunogenic vaccines. Bacterial vaccines containing capsular polysaccharide antigens conjugated to protein carriers are immunogenic, and have been demonstrated to be safe in controlled trials in pregnant women (e.g., Hib)I9, 54 or currently are being studied in this population (e.g., GBS). Viral vaccines produced by isolation and purification of specific antigenic proteins, or by way of the molecular biologic technique of reverse genetics, have shown promising results in in vitro and in laboratory animal models, and some are currently under investigation for use in humans (e.g., RSV, parainfluenza, influenza).

CURRENT RECOMMENDATIONS

Vaccines Currently Indicated During Pregnancy

In the United States, women of childbearing age should be immune to measles, mumps, rubella, tetanus, diphtheria, and poliomyelitis through childhood immunization. Vaccines currently recommended for routine administration to pregnant women in the United States include


the tetanus-diphtheria toxoid and the inactivated influenza virus vaccines (Table 1).

Tetanus Vaccine

Immunization of the pregnant woman with tetanus toxoid at least 6 weeks before delivery effectively protects the newborn against tetanus neonatorum by stimulating the production of specific IgG antibodies that cross the placenta, while also protecting the woman against puer- peral tetanus. Maternal immunization with tetanus toxoid is practiced widely worldwide, and has resulted in dramatic decreases in the incidence of neonatal tetanus in many regions, with no evidence of adverse effects to the mother or fetus.2, 20, 29

Influenza Virus Vaccines

Pregnant women and young infants exhibit increased morbidity with influenza virus inf&tion~.~~, 57 The risk for hospitalization for acute respiratory disease is higher in healthy pregnant women than in young adults with high-risk conditions for influenza. The risk is highest in the third trimester of pregnancy, and in the presence of other underlying ~onditions.5~ Infants under 6 months of age have high infection rates with influenza virus every year, also experiencing the greatest morbidity from influenza illnesses leading to hospitalization.56

Trivalent inactivated influenza virus vaccine (TIV) currently is recommended by the Advisory Committee on Immunization Practices (ACIP) of the CDC for all women who will be in the second or third trimester of gestation during influenza season, and those with underlying high-risk conditions regardless of their stage of pregnan~y.'~ Maternal immunization with TIV is considered safe during any stage of pregnancy, and has not been associated with adverse outcomes in infantsx Pregnant women immunized with inactivated influenza vaccines develop similar immune responses to those of nonpregnant age-matched controls, and transfer vaccine-specific antibodies to their infants effec- t i ~ e l y . ~ ~ Newborns receive high levels of vaccine-specific antibody at birth that can persist for at least 2 months (mean half-life, 35 to 50 days).20 Unfortunately, TIV appears to be largely underused in pregnant women to date, and significant, preventable morbidity continues to occur in the youngest infants.

TIV is prepared from intact, noninfectious, highly purified virus particles produced in embryonated eggs. Current preparations contain whole virus, subvirion, or purified-surface antigens. In infants under 6 months of age and those with debilitating underlying conditions, inactivated vaccines are poorly immun~genic .~~ Live-attenuated influenza vaccines are currently under investigation and are considered safe and immunogenic in healthy adults and children.6 Their use in younger infants (under 6 months), however, remains limited by concerns of safety

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Table 1. VACCINES FOR USE DURING PREGNANCY

Risk of Vaccine IndlcationNaccIne to Fetus

Administer routinely Inactivated influenza virus None reported

(whole virus or subunit)

Tetanus/diphtheria toxoid None confirmed

Administer if indicated in special

Inactivated bacterial vaccinest circumstances*

Meningococcus polysaccharide None reported Pneumococcus polysaccharide None reported Typhoid None confirmed Plague None reported Cholera unknown

Hepatitis A and BS

Rabies unknown

Inactivated virus vaccines 1

None reported

Japanese encephalitis unknown Inactivated poliovirus unknown

Live-attenuated virus vaccines Yellow fever None confirmed Oral poliovirus None confirmed

Measles, mumps, rubella None confirmed Varicella None confirmed

Pneumococcus conjugate Group B streptococcus Meningococcus conjugate Pertussis acellular Respiratory syncytial virus HIV Parainfluenza virus Herpes simplex virus Live-attenuated influenza

Contraindicated

Candidate vaccines

Comments

For all women in 2nd or 3rd trimester of pregnancy during influenza season

Give after 1st trimester of pregnancy when needed

Low efficacy vacine

Indications for prophylaxis not altered by pregnancy

Indications for prophylaxis not altered by pregnancy

Postpone travel preferably

Currently in pregnancy trial

Currently in pregnancy trials

*Residence or travel to endemic areas, exposure, and during outbreak situations. Data in pregnancy not available or limited for most of these vaccines. Should weigh theoretical risk of vaccination against risk of disease.

tHaemophilus influenza type b polysaccharide and conjugate vaccines have been safe and well tolerated in pregnant women, but are not included in current recommendations.

subunit vaccine.


and the immaturity of the immune responses at such a young age. Live- attenuated influenza vaccines have not been tested in pregnant women.

Vaccines Indicated in Special Circumstances During Pregnancy

Pregnant women can be immunized during epidemic or endemic situations with vaccines against poliovirus (inactivated or live-attenuated), hepatitis A, yellow fever, and meningococcus. Vaccines that can be given during pregnancy to women at high risk due to the presence of underlying conditions or probable exposure include the hepatitis B and pneumococcal polysaccharide vaccines.

Poliovirus Vaccines

Oral polio vaccine (OPV) contains live-attenuated poliovirus type 1, 2, and 3, produced in monkey kidney cell cultures. Inactivated polio vaccine (IPV) contains the same viruses grown in either monkey kidney or human diploid celk and inactivated with formaldehyde. Both are highly immunogenic and effective in preventing poliomyelitis. Because of the increased risk of paralytic disease in pregnant women, and the increased risks of fetal mortality and paralytic disease in the newborn,n polio vaccines were routinely administered in the 1950s during pregnancy. Neonates developed antibodies at similar or slightly lower levels than those found in immunized mothers, and were protected from disease.lB A possible association between IPV and some early childhood malignancies was suggested at the time, but has not been confirmed.%

Live OPV was introduced in the early 1960s. Although viremia following irnmunizati~n~~ and cases suggestive of vaccination-associated malformations were reported at the time,12 recent mass immunization programs prompted by poliovirus epidemics in Finland33 and Israel49, 61

failed to show any association between maternal immunization with OPV and congenital malformations or abnormal perinatal outcomes in the infants.32 Although a theoretical risk of adverse effects of IPV or OPV immunization during pregnancy exists, there is no evidence to date that infants born to immunized mothers have increased rates of any adverse event. Routine adult immunization with poliovirus vaccine is not recommended, but immunization with either IPV or OPV of pregnant women at high risk due to endemic or epidemic exposure is recommended by the ACIP and the American Academy of Pediatrics.16*17

Hepa fitis Vaccines

Infants and young children who acquire hepatitis B virus (HBV) infection are at higher risk of serious liver disease and death due to hepatitis and chronic liver disease than adults. Vertical transmission during the perinatal period occurs in infants born to HBsAg-positive

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mothers, and up to 90% of these infants will develop chronic infection. In highly endemic areas, infants born to HbsAg-positive mothers are also at high risk for horizontal transmission and acquisition of chronic HBV infection during their first 5 years of life.17 No specific therapy for HBV infection is currently available.

Preexposure immunization of susceptible persons is the most effective means to prevent HBV transmission. Although plasma-derived HBV vaccines no longer are used in the United States, they are available in other countries. The currently licensed recombinant DNA HBV vaccines containing HbsAg protein adsorbed to aluminum hydroxide are safe and induce a long-lasting protective antibody response in more than 90% of adults. In populations at risk, pregnancy and lactation are not contraindications to vaccination of women. No adverse events on the developing fetus have been observed in vaccinated pregnant women, and infants benefit from the protection of passively acquired antibodies.

Vertical transmission of hepatitis A virus (HAV) infection from mother to infant is rare. Postexposure immunization with HAV vaccine is recommended in adults. Although safety data on pregnant women are limited, the risk to the fetus is considered to be low or nonexistent because the two currently available vaccines in the United States contain inactivated, purified viral proteins obtained from HAV-infected human diploid fibroblast cell cultures.

Yellow Fever Vaccine

Infection with the flavivirus that causes yellow fever results in a mild to severe viral syndrome associated with a high fatality rate. Immunization with live attenuated virus vaccine (17D strain) is recommended for all individuals 9 months or older living or traveling to endemic areas, and is required by international regulations for travel to and from certain countries. In high-risk areas, pregnant women should have been vaccinated with this vaccine, and no adverse events have been reported.67 One possible case of asymptomatic congenital infection (positive serology only) has been reported in a baby from Trinidad, after maternal immunization in the first trimester of pregnancy.82 If travel during pregnancy cannot be postponed, immunization in the first trimester should be avoided if possible.

Meningococcus Vaccine

Pregnant women should be immunized with meningococcal vaccine when there is a substantial risk of infection, such as during epidemics. The vaccine consists of purified bacterial capsular polysaccharides. f i r - 2

ing epidemics in the United States, Brazil, and Gambia, pregnant women immunized with a single dose of quadrivalent or group A and C menin- 1 gococcal polysaccharide vaccine had good antibody responses, transmit- 1 ted the antibodies through the placenta at variable rates (30% to and most importantly, provided protection to their infants during the 1

1


first few months of life.52, 58 Maternal immunization with quadrivalent vaccine has not been associated with adverse events,= or interference with the infant’s responses to active immunizat i~n.~~

Challenges for the Near Future

Currently, the most important bacterial causes of newborn infections in the United States include group B streptococcus and gram-negative enteric organisms. In nonindustrialized countries and certain high-risk groups, Streptococcus pneumoniue and Huemophilus infuenzae type b continue to be a threat. Important viral pathogens in the newborn include respiratory syncytial virus, influenza and parainfluenza viruses, herpes simplex virus, cytomegalovirus, and enteroviruses. Licensed vaccines against some of these pathogens (Hib, pneumococcus) have been tested in pregnant women in recent controlled trials, and found to be well tolerated, minimally reactogenic, immunogenic, and without risk to the mother or fetus?, 19)20, 72

Newer vaccines currently under investigation that potentially could be used during pregnancy include several bacterial vaccines, particularly the group B streptococcal conjugate vaccine and the acellular pertussis vaccine, and viral vaccines such as the live-attenuated influenza virus vaccine, different respiratory syncytial virus vaccines, parainfluenza-3 virus vaccines, HSV vaccinesrn and HIV vaccines. Combination vaccines are also potential candidates for use during pregnancy, possibly increas- ing the number of diseases covered with a smaller number of injections.

Haemophilus lnfluenzae Type b Vaccines

HuernophiZus influenme type b (Hib) vaccines are the model for protection of infants from bacterial diseases through maternal immunization. In the 1980s, Hib capsular polysaccharide polyribosylribitol phos- phate (PRP) vaccines given to pregnant women in the third trimester of pregnancy were shown to be safe and resulted in transmission of vaccine-specific antibodies to the infant’s serum and maternal breast milk.3, z6

More recently, conjugate vaccines (Hib PRP covalently linked to a carrier protein) also have proven to be safe and well tolerated by pregnant women.19, *, 54 In these studies, Hib conjugate vaccines were found to preferentially induce the production of TgGl antibodies, and to confer higher concentrations of antibody to the infant than polysaccharide vaccines. A higher antibody concentration at birth correlated with a greater interval between maternal immunization and delivery; the antibody concentration was greater if the interval was 2 weeks or more. Maternally derived antibodies did not result in tolerance or suppression of the infant’s immune response to active immunization with PRP- tetanus toxoid conjugate vaccinp (see Fig. 1). Recent receipt of tetanus toxoid vaccine was noted to decrease the women’s antibody response

264 MUNOZ & ENGLUND

to PRP capsular polysaccharide that had tetanus toxoid as a protein carrier.”

In regions of the world where Hib vaccine is not available, Hib remains an important cause of meningitis, pneumonia, and bone, joint, and soft tissue infections in infants and children.’ Infants too young to be vaccinated remain susceptible; in the United States, the highest incidence rate of invasive Hib disease (2.2 cases per 100,000 population) occurs in those under 5 months of age.s Maternal immunization with Hib conjugate vaccines could protect infants against severe disease.

Pneumococcal Vaccines

S. pneumoniae is the most common cause of invasive bacterial infections and otitis media in children under 5 years of age. Infections occurring early in infancy are associated with the greatest risk of serious morbidity, mortality, and long-term sequelae. Passive immunization of infants through administration of pneumococcal polysaccharide immunoglobulin and transfer of bfeast milk antibodies from immunized postpartum women reduces infant morbidity from otitis media.71 The protein-conjugate heptavalent vaccine is effective for the prevention of invasive disease in infants during the first year of life when given as part of the routine immunization series, in comparison to the poor response seen in young infants to immunization with the 23-valent pneumococcal polysaccharide vaccine.75, 76 Maternal immunization against pneumococcus is an alternative strategy to protect young infants until they are able to produce an adequate response to active immunization, particularly in high-risk groups.

Pneumococcal polysaccharide vaccines administered to women during the third trimester of pregnancy have been safe for pregnant women and their offspring, conferring modest amounts of circulating antibodies to the h1fant.5~. 68 Pneumococcal conjugate vaccines provide higher antibody responses in adults than the polysaccharide vaccine. Transferring higher levels of antibodies to infants of women immunized during pregnancy would be advantageous, but available conjugate vaccines offer coverage with fewer pneumoccocal serotypes than the licensed polysaccharide vaccine. Maternal immunization with polysaccharide vaccine followed by routine infant immunization with conjugate vaccines would provide broader and longer lasting protection. The implications of modifications in the nasal carriage of pneumococci in infants born to mothers immunized with polysaccharide vaccinesz3 (see Fig. 2), and in babies receiving conjugate vaccine, are yet to be determined.

Group B Streptococcal Vaccines

Group B streptococcus (GBS) is the most frequent pathogen in the neonatal period, and the most common cause of invasive disease in infants under 3 months of age. Women also are susceptible to infection


during pregnancy (chorioamnionitis, endometritis, urinary tract infec- ti0n).4~ A multivalent GBS vaccine would be ideal to provide protection for both mother and infant against disease, most commonly caused by serotypes Ia, Ib, 11,111, and V. Despite the success of prophylactic intrapartum antibiotics in reducing the incidence of early onset neonatal GBS infections,68 the impact of maternal immunization in both maternal and infant disease would be potentially greater, and could decrease the need for antibiotic prophylaxis and its attendant risks.

A GBS polysaccharide vaccine was tested in pregnant women in the 1980s but was found to be poorly immunogenic.4 Single-valent GBS types Ia, Ib, I1 and I11 conjugate vaccines have proven to be safe and immunogenic in dose-response studies performed in healthy adults.5, 41

Type I11 GBS-tetanus toxoid conjugate vaccines and type V GBS polysaccharide vaccines conjugated to different protein carriers have been tested in women of childbearing age, and found to be safe and immunogenic. Animal trials of maternal immunization show promising results,41, 50 and a phase I safety trial is currently in progress.

Acellular Pertussis Vaccines

Despite universal immunization with pertussis vaccine of children under 7 years, the number of cases and morbidity of pertussis in the United States has increased dramatically in recent years, particularly among young Up to 35% of reported cases occur in infants younger than 6 months of age, with a substantial proportion in those less than 3 months of age.14 Most deaths occur in the first month of life. The source of infection in many babies is their mother. The more recently available acellular pertussis vaccines, that can be used in combination with diphtheria and tetanus toxoids, contain immunogens derived from BordeteZla pertussis, and minimal or no endotoxin. Since 1996, they have been used in infants and young children as part of the recommended immunization schedule, and proven to be safe and immunogenic. Acel- lular pertussis vaccines could be considered for immunization of older children and adults when combined with adult diphtheria and tetanus toxoids (Td). To prevent the disease in young infants, women could be offered this booster immunization during prenatal ~are .4~ Studies of the safety and immunogenicity of acellular pertussis vaccines in pregnant women are needed.

*

Respiratory Syncfial Virus Vaccines

Respiratory syncytial virus (RSV) is the most important cause of respiratory disease in young infants ~ o r l d w i d e . ~ ~ Most hospitalized children (over 75%) are under 6 months of age, and approximately half are under 3 months of age.3l Efforts to prevent serious RSV disease should be targeted during these first months of life.

In the 1960s, infants immunized with a formalin inactivated whole- virus RSV vaccine were noted to develop more severe disease at natural

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RSV infection than randomized c0ntrols.3~, 44 This paradoxical response proved to be unrelated to the presence of neutralizing RSV antibodies, and studies in animal models have offered convincing evidence of the protection conferred by RSV-specific antibody.", 84 Clinical studies have failed to demonstrate a relationship between the severity of illness and the levels of RSV antibody titers,'O and multiple studies have demonstrated that high levels of maternally derived antibodies protect infants from severe RSV disease.2B, 40, a, 85 Furthermore, intravenously administered high-titered RSV immunoglobulin79 or RSV-specific monoclonal antibody80 have demonstrated both safety and protection from serious RSV disease in high-risk infants.

Live RSV vaccines have been found to be too virulent or too attenuated and poorly immunogenic in infants younger than 6 months of age.15 The availability of methods to purify the antigenic RSV surface glycoproteins (F and G) has enabled the development of RSV subunit vaccines (PFP-1 and PFP-2; Lederle Praxis Laboratories, Pearl River, NY) from the A2 strain of RSV. Antibody to the F protein correlates with immunity to RSV!O In healthy children, these vaccines are nonreacto- genic and immunogenic, and effective in preventing severe RSV disease in high-risk children.'j2, 63 The presence of PFP vaccine-induced antibodies has not been associated with serious disease after natural infection with RSV.7, 81 A live-attenuated RSV recombinant vaccine developed with reverse genetics techniques (BBG2Na) also has been shown to provide immunity in an animal model of maternal immuni~ation,~~ and this and other live-attenuated vaccines currently are being evaluated in phase I clinical trials.

If women were immunized during pregnancy, these RSV vaccines could provide protection to the newborn and young infant through passively acquired neutralizing antibody. Following maternal immunization, live attenuated vaccines could be used in older infants, when they are more apt to respond adequately to the vaccine. This approach has been studied in animal models with various RSV vaccines and immunizing regimen^.^, 11, 78 In clinical studies of healthy postpartum women, the PFP-2 subunit vaccine has been found to be minimally reactogenic (fewer side effects than the influenza vaccine), immunogenic in 90% of recipients, and eliciting preferencially IgGl subclass anti-F protein antibodyB3 IgG and IgA antibodies to the F protein also have been detected in breast milk. A phase I trial with the PFP-2 vaccine in pregnant women is currently in progress.

Parainfiuenza Virus Vaccines

Live attenuated parainfluenza virus vaccines developed by reverse genetics methods have been developed and are under evaluation for the prevention of respiratory tract disease caused by these viruses in children. Vaccine candidates under evaluation include a cold-adapted, temperature-sensitive, attenuated strain ( ~ ~ 4 5 ) : ~ and a P1V3 vaccine derived from a wild-type bovine PIV and similarly a t t e n ~ a t e d . ~ ~ , ~ ~ These vaccines


have been shown to be safe and immunogenic in seropositive children and adults, and studies in seronegative infants are in progress. If used during pregnancy, these vaccines or new subunit vaccines could prevent yet another important illness in young infants.

SUMMARY

The concept of maternal immunization to prevent infectious diseases during a period of increased vulnerability in the infant is sup- ported by historical experience and carefully conducted studies of various viral and bacterial vaccines. Candidate vaccines should be minimally reactogenic, immunogenic, and safe. Health education and access to immunization should be a priority if maternal immunization is to suc- ceed as a disease prevention strategy. The potential effect on the incidence of disease in the newborn and young infant can only increase as more candidate vaccines that could be administered during pregnancy become available. In the future, common infections and other, more dreaded diseases, such as herpes simplex virus infection, cytomegalovirus, and human immunodeficiency virus infection, could be prevented with this intervention. Further research on the safety and efficacy of maternal immunization must continue if the occurrence of serious infectious diseases in neonates and young infants is to be reduced.

ACKNOWLEDGMENT

The authors acknowledge W. Paul Glezen, MD, for critical review of this article. Financial Support: Contract No. AI 65316 awarded by the National Institute for Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US government. Informed consent was obtained from the patients or their parents or guardians. Guidelines for human experimenta- tion of the US Department of Health and Human Services and those of the authors' institutions were followed in the conduct of clinical research.

References

1. Adegbola PA, MulhoUand EK, Falade AG, et a1 Hamnophilus influenzae type b in the western region of The Gambia: Background surveillance for a vaccine efficacy trial. Ann Trop Pediatr 16102-111,1996

2. Amstey MS: The potential for maternal immunization to protect against neonatal infections. Semin Perinatol 15:20&208, 1991

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Address reprint requests to Flor M. Munoz, MD

Department of Microbiology and Immunology Baylor College of Medicine Room 221-D

One Baylor Plaza Houston, TX 77096

e-mail: [email protected]

167191-195, 1993

Vaccines in Pregnancy

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