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Isolation of Attenuated Rubella-Vaccine Virus from Human Products of Conception and Uterine Cervix
Abstract
To evaluate the fetal hazard of accidental administration of live rubella vaccine during pregnancy, the vaccine was given to 35 women certified for legal abortion. Twenty-four of these were rubella seronegative. Various specimens, including the products of conception, were tested for rubella virus independently in three collaborating laboratories. Rubella virus was recovered from the placenta in six cases and from the fetus in one case. Virus was also found in 13 of 22 uterine cervical swabs taken nine to 25 days after vaccination of seronegative mothers. Virus was not isolated from comparable specimens obtained from women with pre-existing antibody. The results indicate a hazard of placental and fetal invasion by the vaccine virus and emphasize the need to observe precautions when post-puberal female patients are vaccinated.
... Reactivation and reinfection of the virus was postulated as the earlier vaccines often produced rubella-like symptoms in the recipients [34,35]. Furthermore, the presence of virus in placental specimens of women who had received the vaccine raised concern regarding teratogenic potential of the vaccine [36]. ...
As we live through the history-making pandemic of coronavirus disease 2019 (COVID-19), it is timely to consider the lessons that history has taught us about vaccine-preventable disease in pregnancy. Vaccinations have earned an established place in pregnancy care to prevent communicable disease in the mother, fetus and newborn. The improvements in maternal and perinatal outcome have been achieved through the evolution and application of new knowledge in many areas. These include recognition of the unique pathogenic consequences of diseases in pregnancy; improved understanding of the maternal immune system and its interplay with the fetus; optimizing safe vaccine development; ensuring pregnant women are included in appropriately designed trials of efficacy, and public health engagement to optimize uptake. As the world eagerly awaits an effective vaccine for COVID 19, these lessons of history help signpost the way, to ensure the potential of vaccinations to reduce morbidity for pregnant women and their newborns is fully realized.
... Evidence has been presented in tropical spastic paraparesis patients that antibody mimicry and activation of cytotoxic T cells by the TAX protein are participating in the pathogenesis of HTLV-1 associated autoimmune myelopathy (Domínguez et al. 2008; Nakamura, 2009). It has been also clarified as early as in 1969, that the attenuated rubella vaccine virus can pass the placenta, can be isolated from the fetal tissues, but no rubella syndrome was ever caused by the MMR vaccine virus (Vaheri et al. 1969Vaheri et al. , 1972 Bozzo et al. 2011). Evidence has been provided against the association of autism with either MMR or a single measles vaccine (MrozekBudzyn et al. 2010). ...
Current treatments for various degenerative disorders rely on surgical interventions and drugs that modulate the system, but these have their own limitations when it comes to regeneration of damaged tissues and cells. To address this shortcoming, cell-based therapies are gaining importance. Adult stem cells have generated great amount of interest amongst the scientific community for their potential therapeutic applications for unmet medical needs. Haematopoietic stem cells and MSCs are the two widely studied and characterized adult stem cells. Mesenchymal stem cells as a choice for cell-based therapies in regenerative medicine are becoming very clear.
... 1 Unfortunately, the vaccine virus was able to pass the placenta, and might also have been able to cause infection of the fetus. 2 Thus, implementation of the Rubella virus vaccine by offering vaccination to young girls, at the age of 12-13 years, was most natural-the early adolescent girls were not likely to become pregnant and were effectively protected against Rubella for the forthcoming years of fertile age. ...
... Although the teratogenicity of attenuated rubella virus strains incorporated in currently licensed vaccines is unknown, it has been shown that, if administered during pregnancy, vaccine strains may infect the conceptus (Phillips et al., 1970; Larson et al., 1971; Ebbin et al., 1972; Vaheri et al., 1972). Much fetal wastage has occurred since pregnancies have frequently to be terminated after inadvertent vaccination during pregnancy, often without earlier determination of the vaccinee's immune State (Mair and Buchan, 1972). ...
Japanese strains of rubella virus have been claimed not to be teratogenic, and tests on three Japanese strains showed that they induced high levels of interferon in human placental cell cultures obtained from conceptuses ranging from 13 to 24 weeks' gestational age, whereas two strains derived from the U.S.A. induced low levels. Both Japanese and U.S. strains induced similar but low levels in fetal lung cell cultures and leucocyte preparations. A representative Japanese strain and a U.S. strain were both interferon-sensitive. If indeed a strain can be shown to be non-teratogenic it could lead to an alternative, safer rubella vaccine.
Prenatal infections are common and varied. Their pathogenesis and related circumstances must be understood if the pathological lesions are to be interpreted correctly, and although many types of infection cause placental changes, in some types, the infection may be difficult to prove from placental examination alone. Infections may ascend from the endocervical canal, or they may reach the placenta hematogenously through the maternal blood. Rarely are they iatrogenic and acquired by amniocentesis, chorionic villus sampling, amnioscopy, percutaneous umbilical blood sampling (PUBS), or intrauterine fetal transfusion. Rare cases may also develop from direct infection from the endometrium. Many infections cause gross and microscopic changes of the placenta, but others, e.g., most cases of Coxsackie virus infection, leave few characteristic or specifically recognizable traces. This is also the case with parvovirus B19 infection, which often leads to fetal hydrops but has no specific placental alteration other than the classic intranuclear inclusions in nucleated red blood cell precursors and endothelium (Hartwick et al. Teratology 39:295–302, 1989). Rarely both Coxsackie and parvovirus B19 (Samra et al. Obstet Gynecol 73:832–4, 1989) do result in lesions (see discussions below).
As noted earlier in reference to both performance of studies on fetal endocrinology and steroid metabolism, and in reference to other “experiments” for “pure science” and the conduct of double-blinded clinical trials in attempting to improve survival of very premature infants, a number of questions have arisen in regard to the ethics of experimentation. In addition to the issue of the culture wars of abortion, debates about the fetus, whether it be their bodies, rights, personhood, or perception of pain, involve arguments of scientific authority, political, religious, and social values, as well as other considerations (Dubow 2011; Morgan 2009; Reagan 2010). In addition, with the lifesaving technologies of maintaining viability of premature infants at ever earlier ages, and the recognition that a high percentage of such newborns face a life of neurologic disability, the debates can become intense. A number of gifted individuals have addressed these issues, and there are no easy answers. In his banquet address upon receipt of the 1949 Nobel Prize for Literature, in the early years of the Cold War era William Faulkner addressed the tragedy of that day, that of an almost universal fear for life and survival and our universal need for compassion and perseverance. In part, this involves our gaining an understanding of our origins.
United Kingdom and United States programmes of active immunization for the prevention of rubella during pregnancy are compared and their respective advantages and disadvantages discussed. The need for revaccination is more likely to arise with the United States programme in which young children are vaccinated and where, in future, immunity in adults will become increasingly vaccine-induced.
Rubella was first recognized as a distinct disease entity in the early 1800’s (68). For the next 125 years, rubella virus was considered to cause only a mild morbilliform rash, occasional fever and a rather predictable lymphadenopathy. Predominantly a childhood disease, rubella is endemic throughout the world and is associated with epidemics which occur every six to nine years.
The cytologic features of cervical infections vary with the nature of the tissue lesion and the chronicity of the infective process; most commonly observed are nonspecific destruction of epithelial cell and inflammatory and immunologic reactions of the stromal layer. During physiological metaplasia the cervical epithelium appears inflamed and shows leukocytic infiltration. Bacteriologic studies of such lesions often yield disappointing results, with either the presence of nonpathogenic organisms or an absence of organisms (Singer and Jordan, 1976).
Rubella was initially recognized as a distinct disease entity in the early nineteenth century1. For nearly 150 years, rubella virus was considered to cause only a mild morbilliform rash, occasional fever and a rather predictable lymphadenopathy. Predominantly a childhood disease, rubella is known to be endemic throughout the world and is associated with epidemics which occur in irregular fashion.
As noted earlier in reference to both performance of studies on fetal endocrinology and steroid metabolism, and in reference to other “experiments” for “pure science” and the conduct of double-blinded clinical trials in attempting to improve survival of very premature infants, a number of questions have arisen in regard to the ethics of experimentation. With the lifesaving technologies of maintaining viability of premature infants at ever earlier ages, and the recognition that a high percentage of such newborns face a life of neurologic disability, the debates can become intense. A number of gifted individuals have addressed these issues, and there are no easy answers (Fig. 16.1).
Prenatal infections are important aspects of placental pathology. They are common and varied. Their pathogenesis and related circumstances must be understood if the pathological lesions are to be interpreted correctly. Many types of infection cause placental changes, but in some types, the infection may be difficult to prove from placental examination. Ultrastructural studies are especially lacking in this area and might be helpful, particularly when virus infection is suspected. Infections may ascend from the endocervical canal, or they may reach the placenta hematogenously through the maternal blood. Rarely are they acquired by amniocentesis, chorionic villus sampling, amnioscopy (Horky and Amon 1967), percutaneous umbilical blood sampling (“PUBS”; Wilkins et al. 1989), or intrauterine fetal transfusion (Goodlin 1965; Scott and Henderson 1972). Many infections cause gross and microscopic changes of the placenta, but others, e.g., the Coxsackie virus infection, leave few characteristic or specifically recognizable traces. This is also the case with parvovirus B19 infection, which often leads to fetal hydrops but has no specific placental alteration other than perhaps intranuclear inclusions in nucleated red blood cell precursors and endothelium, as a report by Hartwick et al. (1989) showed. Samra et al. (1989) described villous necrosis and calcification in the placenta from a 20 weeks’ gestation with hydrops due to this infection (see Chap. 16).
There are good reasons to draws parallels between the vaccines against the four diseases measles, mumps, rubella, and varicella. Each is a classical systemic childhood disease, and infection with wild-types of each of these viruses bequeaths a life-long protection upon renewed exposure to the infectious agent. Furthermore, live vaccines effectively preventing each of these tour diseases have been developed by empirical techniques. However, there are also important differences in pathogenic events connected with the acute diseases caused by these agents.
Rubella (German measles) is a common contagious disease with mild constitutional symptoms and a generalized rash. In childhood it is an inconsequential illness, but when it occurs during pregnancy there is a significant risk of severe damage to the fetus.
Prenatal infections are an important aspect of placental pathology. They are common and varied. Their pathogenesis and related circumstances must be understood if the pathological lesions are to be interpreted correctly. Many types of infection cause placental changes, but for some types the infection may be difficult to prove from placental examination. Ultrastructural studies are especially lacking in this area and might be helpful, particularly when virus infection is suspected. Infections may ascend from the endocervical canal, or they may reach the placenta hematogenously through the maternal blood. Rarely are they acquired by amniocentesis, chorionic villous sampling, amnioscopy (Horky & Amon, 1967), percutaneous umbilical blood sampling (Wilkins et al., 1989), or intrauterine fetal transfusion (Goodlin, 1965; Scott & Henderson, 1972). Many infections cause gross and microscopic changes of the placenta, whereas others (e.g., Coxsackie virus infection) leave few characteristic or specifically recognizable traces. This point is also the case with parvovirus B19 infection, which often leads to fetal hydrops but has no specific placental alteration other than perhaps intranuclear inclusions in nucleated red blood cell precursors and endothelium, as a report by Hartwick et al. (1989) showed. Samra et al. (1989) described villous necrosis and calcification in the placenta from a 20 weeks’ gestation with hydrops due to this infection (see Chapter 16).
The maternal immune system is modulated by many factors during pregnancy. The maternal-fetal transmission of viruses and its consequences is changing during the different phases of pregnancy. Gestational age is influencing the consequences of the contact with viruses and viral antigens. In addition to the factors of innate immunity, virus receptors, factors of elicited cellular and humoral immunotolerance, humoral and cellular fetal responses to viral antigens and sensitisation of fetal immune cells are modulated during pregnancy. The role of transplacental transport of nanoparticles, immunocomplexes by maternofetal active transport were shown to facilitate fetal damage during pregnancy. The viruses molecularly integrated into the sperm cells, or their passive adsorption to the sperm cells will be discussed in other chapters of the volume. Permissiveness of cytotrophoblasts or syncytiotrophoblasts to the virus is the simplest way of vertical maternofetal infections. Reactivation of the viruses in seropositive pregnants may facilitate the transfer of infective immunocomplexes into the fetal circulation. Molecular transcytosis was found to be an important route of vertical transmission of viruses discussed in an other chapter of the monograph. In the case of genital infections, the ascending infections may be the source of fetal damage. The definition of perinatal transmission is the virus contamination of the newborns during delivery. Breast feeding is an important risk factor in the case of several viruses. Available preventive and therapeutic measures are mentioned in the chapter.
Epidemic situations and the prospect of overseas travel are increasingly posing the problem of whether or not to offer immunisation to pregnant women. Several papers have been published on the relative risks to mother and fetus of exposure to attenuated vaccine strains as compared with virulent wild strains. A review of these publications suggests that immunisation against poliomyelitis and yellow fever is indicated in women contemplating travel to affected areas; for rubella and mumps vaccination and routine smallpox vaccination pregnancy is a contraindication, but vaccination (with immune-globulin cover) should be mandatory for the pregnant woman travelling to a smallpox-endemic area; measles vaccination is not indicated in pregnancy.
In this paper the argument is made that in utero experimentation which results in abortion is permissible. The discussion then turns to some troubling questions raised by this sort of research. Chief among these are questions concerning limitations placed on the autonomy of the women involved. The argument is made that women ought not change their minds regarding abortion once research has begun. Other issues discussed include objecting to this sort of research on the grounds that it presents a harm to the fetus and whether programs of in utero research condone the practice of abortion.
Pregnant and lactating hamsters were inoculated with reovirus type 3 and H-1 virus to determine whether they had any special susceptibility as compared with nonpregnant controls; whole blood, liver, and uterus were tested for virus on successive days after inoculation. Results showed that both agents proliferated to highest titers in pregnant as well as in lactating animals. These results were most striking with reovirus, which propagated to only a limited extent in controls and hamsters in the first half of gestation, although developing to high titers in the second half. A feature of the experiments was the ability of both agents to infect the postpartum uterus. Uterine infections, which appear to have importance for both rubella and cytomegaloviruses, should it would seem, be considered in relation to any viruses capable of inducing fetal infections or congenital anomalies.
Recent advances in the diagnosis and prevention of rubella are reviewed. The following are considered: rubella infection in pregnancy and the expanded rubella syndrome; serological diagnosis in the mother and newborn; the place of gamma globulin; the development and side-effects of rubella vaccines; immunization programmes and their limitations; whether live, attenuated rubella virus given just before or during pregnancy is teratogenic; how to investigate such patients and avoid such mishaps; problems with vaccination in the puer-perium; and the place of routine tests for rubella in pregnancy.
MATERIALS AND METHODSRESULTSDiscussionACKNOWLEDGEMENTSReferencesDiscussionReferences
The case histories of 65 women whose pregnancies were complicated by the inadvertent administration of rubella vaccine are described. In 36 the pregnancy was terminated. Spontaneous abortion occurred in 3. Nineteen women were delivered of normal infants and in 7 the birth is still awaited. No virological or clinical evidence of fetal infection or abnormality was found. The pre-vaccination immune status of most of the women was unknown. Adequate assessment of the effect of rubella vaccination on pregnancy will only be possible when many more such cases are studied.
Rubella virus (RV), a positive-stranded RNA virus, is the only member of the genus Rubivirus within the Togaviridae family. The virus consists of a host derived lipid bilayer membrane, membrane glycoprotein spikes, and the C protein which together with viral RNA forms the icosahedral nucleocapsid. Although clinical rubella is a relatively mild disease, RV remains an important human pathogen because of its teratogenic effects in utero which can result in new born infants with congenital rubella syndrome (CRS). Complications such as polyarticular arthralgia and arthritis following vaccination or infection are common and rare cases of progressive panencephalitis have been reported. To obtain a better understanding of the immunopathology of RV infection, the degree of antigenicity of the structural proteins in humans were examined for both cellular and humoral immune responses. It was found that of the structural proteins, El glycoprotein was the dominant antigen recognized by the study population sampled from normal individuals with no history of rubella associated conditions. It was also found that the CRS patients had immune responses distinct from that of the normal population. In CRS patients E2 was the dominant antigen to which both cellular and humoral immune responses were elicited. The implications of these observation with respect to proposed mechanisms of persistent infection are discussed. Twenty three synthetic peptides spanning the entire El sequence were screened with human peripheral blood lymphocytes and the corresponding sera to examine the distribution of antigenic domains. El glycoprotein was also the target of viral neutralizing (VN) and hemagglutinin (HA) epitope mapping studies. Deletion mutants of El were constructed from El cDNAs and expressed in in vitro, in COS cells and in E.coli. The mutants were screened with monoclonal antibodies with VN and HA inhibiting activities. The mutants containing the functional epitopes were further studied by using synthetic peptides. HA epitope was mapped to amino acid residues E1214 to E12„ while two VN epitopes mapped to amino acid residues E1214 to E12, and E1219 to E1232. The potential use of the defined epitopes in the development of subunit vaccine is discussed.
This chapter is concerned with virus vaccines and their genetically conditioned markers. For many years, virus vaccines have been in fact the only effective means for reducing the morbidity of virus infections, and thus far biogenic, semisynthetic, and synthetic antiviral substances have failed to give satisfactory results. Although a number of compounds are known to be active in vitro, their application in vivo is limited, mainly because of a very close relation between the molecular events of virus replication and cell metabolic processes. Active immunoprophylaxis has quite a long history (variolation), but its scientific application was initiated by the fundamental discoveries of Jenner and Pasteur. Four of the attenuated virus vaccines now in widespread use are prepared in cell cultures in vitro: poliomyelitis, measles, mumps, and rubella vaccines. Since these vaccines share certain analogous features of viral replication and attenuation during culture, experience gained in the study of one vaccine can be applied to studies of the others. Adaptation of strains of polio, measles, mumps, and rubella viruses to cells in vitro permitted a new approach to the preparation of highly active virus vaccines. Nevertheless, it has also introduced new problems and created new possibilities for the assay of virus characters during the attenuation process and for the selection of mutants with desirable sets of characters. There must be a means of constant evaluation of the vaccine strains and progeny virus generations by specific features and characters in vitro and in vivo. These genetically conditioned “markers,” and the problems related to the assay and application of the markers are the subject of this review in this chapter.
To determine the susceptibility of the postpartum and postabortal genital tract to infection with attenuated rubella virus, 30 patients with negative hemagglutination inhibition (HI) titers were studied. Following inoculation with Cendehill or RA 27/3 vaccine, viral cultures of the cervix and uterine cavity were obtained with blood specimens to evaluate serologic conversion. Attenuated rubella virus was not isolated in any patient; seropositive conversion was achieved in 24 women. The significance of these findings related to wild rubella virus infection is discussed.
A total of 21 rubella seronegative children vaccinated subcutaneously with Wistar RA 27/3 strain live attenuated rubella vaccine in a family study of vaccine virus transmissibility were reviewed after 6 years. Haemagglutinating inhibiting (HAI) antibody titres of sera collected 46 days, 2 years and 6 years after vaccination were compared. Antibody titres in the vaccinated subjects were not significantly influenced by time, infection in susceptible siblings or revaccination.
Many new facets of rubella virus infection, both natural and congenital, have been recently exposed. In its intrauterine role, the virus is curiously selective and it is possible that the genes of the fetus are important in determining both the occurrence and severity of infection. The risk to the fetus is highest if infection occurs in early pregnancy, but there is some risk up to 24 weeks gestation. Multiplicity of defects and chronic persistence of fetal infection are characteristic features of congenital rubella infection. The clinical manifestations, diagnosis and management of congenital rubella are discussed, with emphasis on the long term sequelae. Postnatal rubella may be difficult to diagnose, since many cases are subclinical and history is unreliable:— serological diagnosis is therefore critical during pregnancy. Vaccination programmes designed to prevent congenital rubella are evaluated; while these show promise, the ideal vaccine is yet to become available.
Despite extensive use of atttenuated rubella vaccine during the past five years, the degree of fetal risk in susceptible women inoculated early in pregnancy is still an unresolved issue. Although there is considerable evidence of chronic vaccine virus infection of the products of gestation in aborted fetuses, congenital defects have not yet been reported in the newborn infants of susceptible vaccinated pregnant women. The normal findings in the newborn infant can be misleading with respect to the safety of the vaccines in early pregnancy, because they represent only a small selected group of reported cases. The immediate need is for more complete reporting of all relevant cases wherever they occur in order to determine without many more years of delay whether the fetal risk has public health significance or is so low as to be of negligible importance.
Antibody and cell-mediated immunity (CMI) was measured in rabbits immunized with wild or attenuated virus and in rabbits vaccinated with a rubella subunit vaccine containing the viral envelope or nucleocapsid.
The data presented show that a subunit vaccine containing the envelope proteins could induce a good antibody and CMI response.
The results also suggest that such a vaccine was highly effective since 60 per cent of the rabbits immunized with the envelope proteins were protected when challenged with wild virus. This protection rate was identical as the protection achieved with a live attenuated vaccine.
Better understanding of cell-mediated immune responses to rubella virus would provide the basis for the development of safe and effective vaccines against rubella and would aid in analysis of the pathophysiology of congenital rubella syndrome. We have expressed individual rubella virus structural proteins, E1, E2 and C, via vaccinia virus recombinants. Using the expressed recombinant proteins as antigens, we were able to demonstrate antigen-specific lymphocyte proliferative responses in control individuals and individuals with congenital rubella syndrome. Among the two human groups studied, E1 glycoprotein proved to be a better immunogen than E2 or C. For the control individuals, significant differences in proliferative responses to the structural proteins E1, E2, and C were observed. These differences were not significant in individuals with congenital rubella syndrome. In parallel to the lymphoproliferative responses, immunoglobulin G responses were also found directed mainly to the E1 glycoprotein. These results suggest that E1 may be the most important rubella virus antigen to study in determining the domains required for constructing subunit vaccines against rubella.
A survey done after a severe epidemic of measles in an urban area of Guinea-Bissau has shown that children born to women exposed to measles during pregnancy had a perinatal mortality rate of 15%, compared with only 4% for other children in the community (OR = 4.2; 95% CI 2.1-8.5). None of the women had clinical evidence of measles. Adjusting for background variables, logistic regression analysis showed no tendency towards reduced risk of perinatal mortality among children of women exposed during pregnancy relative to controls. Both stillbirth and early neonatal mortality rates were increased. A similar tendency was found in a rural epidemic (OR = 9.5; 95% CI 2.6-35.1). Exposure during any trimester of fetal life increased the rate of perinatal mortality. The results suggest that exposure to measles virus or some concomitantly transmitted pathogen may contribute to the high perinatal mortality risk found in many developing countries. The possible long-term health consequences of exposure to measles virus should be considered when assessing the value of measles control programmes.
Although there does appear to be at least a temporal relationship between pertussis immunization and serious acute neurologic illness, data to suggest that children with stable preexisting neurologic disease or positive family history of neurologic disease are at increased risk for complications of pertussis immunizations are inconclusive. Furthermore, there are no firm statistical data concerning the incidence of pertussis vaccine-related encephalopathy. Rather, the literature on pertussis vaccine complications is replete with anecdotal reports and retrospective studies with a number of questionable conclusions drawn from this inadequate data base. Unfortunately, these conclusions have been sensationalized and exploited with litigious fervor to the point that the practice of pertussis immunization is being questioned in the United States. A number of points should be reiterated: pertussis is a dangerous and deadly disease, as seen in the epidemic in Great Britain; pertussis immunization is effective in protecting against the disease; and there is no conclusive proof that the incidence of complications from pertussis vaccination of children with seizure disorders or other preexisting stable neurologic abnormalities is higher, because appropriate studies have not been done to define such a risk. We would do well to keep these facts in mind in order to avoid a disaster similar to the pertussis epidemic in Great Britain. Pertussis vaccination should be given to all children except those with allergic hypersensitivity, a progressive neurologic disorder, or an adverse reaction to a previous pertussis dose.
Immunization practices are frequently changing as our understanding of the basic concepts of host-parasite interactions grows and research in the area of new vaccines continues. The present review attempts to summarize current practices and the scientific data on which they are based. A complete historical review of the subject is beyond the scope of this report which is only intended to survey developments in the field over the past few years and up until October 1972.
Rubella virus was isolated from the uterine cervix in two of three nonpregnant women 2-6 days after the onset of clinical rubella infection. Viral invasion of cervical secretions was demonstrated when titres of circulating antibodies were high. Thus, local rubella infection may involve the risk of intrauterine rubella infection in early human embryos. The findings indicate the advisability of effective contraception for some time after rubella infection.
Several comprehensive reviews and compendia of immunizing biologicals currently available or under development have recently appeared in the medical literature. In addition to these useful references the United States Public Health Service and the American Academy of Pediatrics periodically publish revised and updated recommendations on immunization practices. In the present, selected topics in immunization are considered in an attempt to supplement rather than duplicate the material presented in these other publications.
Of 2124 women delivered of their first child in the Oxford region in 1963, 21 conceived again within 90 days of delivery. 20% of these women would be expected to be seronegative. Vaccination of seronegative primiparous women against rubella during the immediate post-partum period may put early second pregnancies at risk. Post-partum vaccination should be done as soon as possible after delivery, and should be accompanied by contraceptive measures for 2-3 months.
THE CURRENT candidate strains of attenuated rubella vaccines have proved capable of eliciting a demonstrable antibody response. At their present level of attenuation all the strains are known to cause viremia and virus shedding from the respiratory tract, although no transmission of the vaccine virus to susceptible contacts has been demonstrated with certainty. In addition to the potential communicability of attenuated rubella virus from a vaccinee to a pregnant mother, the danger exists of accidental vaccination during pregnancy. This has prompted our studies on the transplacental passage of attenuated rubella vaccines in humans.Materials and Methods
The general scheme of the study is shown in Table 1 and the Figure. The vaccinees were patients from the department of obstetrics and gynecology, University of Helsinki or The State Institute of Midwifery, Helsinki. As of January 1969, 32 patients have received by subcutaneous inoculation (1 ml) either HPV-77-DK12 (dog kidney grown) rubella
Six hundred and thirty six families including 1,686 children participated in a trial of HPV-77-derived live attenuated rubella virus vaccines. Transmission of vaccine virus was not observed among 347 susceptible household contacts of vaccinated children. The observed absence of transmission of vaccine virus indicates that vaccination of children is unlikely to represent a hazard to their pregnant mother. Antibody levels induced by vaccination were lower than those induced by natural disease. Statistically significant differences in antigenic efficacy were observed among the three vaccines tested. The paucity of data so far available on long-term protection afforded by vaccination and on susceptibility to reinfection among vaccines and its significance make it advisable to continue the surveillance of children that participated in controlled trials.
THREE trials were conducted in Nagoya, Japan, testing the safety, antigenicity, contagiousness, and transplacental passage of RA27/3.
Trial 1 was performed with children in a closed orphanage and with nurses attached to two hospitals in Nagoya. Most of the 43 seronegative subjects in the orphanage were between 1 and 2 years of age, with a range from 8 to 35 months. The other subjects were 16 adult women whose ages ranged from 19 to 25 years. In the orphanage, seven rubella susceptible uninoculated children were placed in two rooms where there was ample opportunity for close contact with inoculated children, while playing and napping together.
In the other two trials, the subjects were selected from nursing students at another hospital; 105 were seropositive, and 21 were seronegative. The total number inoculated in the three trials, therefore, included 80 seronegative and 111 seropositive subjects. Of the seronegative subjects, 37 were
Rubella-susceptible women in the childbearing age will need and will request rubella vaccine for direct protection until the spread of rubella is controlled by the immunization of children. Immunization of women should be performed on an individual basis, and appropriate measures should be taken to avoid administration of vaccine shortly before or during pregnancy. This case series of 17 women in California who inadvertently received rubella vaccine shortly before or during pregnancy from April 1969 through February 1970 points to the need for both physicians and patients to be more acutely aware of this problem.
During a state-wide rubella immunization campaign, nearly 100,000 children received vaccine. Of 1,350 pregnant women screened serologically before and during the campaign, 13% were found to be susceptible. Follow-up serological studies on 121 of the susceptible group, which included 31 close contacts of vaccinees, revealed only one instance of seroconversion. This patient, who was clinically asymptomatic, could not be related temporally to an immunized child in the home or to any other identifiable exposure. Such data support the view that susceptible pregnant women in close contact with vaccinees are as unlikely to acquire infection as are susceptible siblings or nonpregnant women.
FETAL death and malformation of the newborn associated with a substantial increase in rubella cases is anticipated in the United States in 1970 or 1971. The best means for preventing this event is in the proper application of an effective vaccine. The vaccine might be given either to children alone, en masse, to decrease the rubella reservoir, or to susceptible adult women as well.
The HPV-77 rubella virus1,2 propagated in cell cultures of duck embryo3-13 has been the most extensively tested of all the candidate rubella vaccines to date. This vaccine proved highly effective in evoking rubella antibodies in children without causing detectable clinical reaction and without contagiousness to susceptible children or to maternal contacts.
Contrary to the findings in children, a portion of adult women9 who received the HPV-77 vaccine developed mild rubella with arthritis and arthralgia. It became important, therefore, to determine the age range