Outbreak of measles among persons with secondary vaccine failure, China, 2018

ABSTRACT

Although the incidence of measles has been dramatically reduced by the highly effective measles vaccine, cases of measles and outbreaks continue to occur in vaccinated population because of immunization failure. We report on an outbreak in which two cases had previous evidence of measles immunity and then one of them transmitted measles infection to an unvaccinated contact. The cases and contacts exposed during the outbreak were investigated. Clinical information and epidemiological information were obtained. Serum samples were collected for measles-specific immunoglobulin M (IgM), immunoglobulin G (IgG) and IgG avidity. Throat swabs were obtained to test for measles virus RNA. Two measles cases (case 1 and case 2) who have received one dose of MCV in past 5 years, and both working at a hospital in Beijing, occurred in 18^th and 20^nd of January, respectively. Out of the 102 contacts, one additional case (case 3) who had a close, long-term co-exposure with case 1 was reported subsequently. No additional cases of measles occurred among 15 contacts of case 3. The index case was not ascertained through the outbreak review. All three cases had laboratory confirmation of measles infection. Both case 1 and case 2 had high-avidity IgG antibody characteristic of a secondary immune response and developed a modified clinical presentation. This report confirms that a vaccinated individual with documented secondary vaccine failure (SVF) could transmit measles and is the second report since a New York City outbreak (the first report in China). The outbreak represented a series of rare events, so we can conclude that the SVF individuals in the transmission chain of measles are unlikely to threaten measles elimination. The importance of the herd immunity in preventing transmission and sensitive surveillance activities in case of misdiagnosis is emphasized.

Introduction

Measles is a highly infectious disease with serious complications that causes enormous morbidity and mortality among children in many parts of the world. Before the introduction of measles vaccine, an estimated 2 million deaths occurred globally each year, and more than 95% of individuals had been infected with measles virus by the age of 15 years.¹

Since the availability of safe and effective vaccines in the 1960s, widespread vaccination of children in America and other countries has had a dramatic effect on the incidence of measles and its associated complications.^2–4 As the reductions in morbidity and mortality have been so great, a conference was held by World Health Organization (WHO), Pan American Health Organization, United States Centers for Disease Control and Prevention (CDC) to discuss the improvement of measles control in 1996 and global elimination has been proposed and judged feasible.⁵ In 2016, measles has officially been declared eliminated from the Region of the Americas of WHO.⁶

Although vaccination is highly effective and a proxy for immunity to measles, cases of measles and outbreaks continue to occur in vaccinated population because of immunization failure, especially secondary vaccine failure (SVF).^7,8 An outbreak of measles in New York City spreading from a measles case with a verified secondary immune response has been reported in 2011.⁹ In China, a measles outbreak in a middle school in 2014 demonstrated the transmission probably due to a secondary immunization failure patient with the documented receipts of three doses measles-containing vaccine (MCV), but the direct laboratory testing evidence was not acquired.¹⁰ Recently, SVF attracts more public attention gradually and it is necessary to understand the characteristics of SVF patients and how they transmit for guiding elimination of measles.

Here, we report on an outbreak of three cases of measles in China in which two cases had previous evidence of measles immunity and then one of them transmitted measles infection to an unvaccinated contact.

Methods

Case identification and investigation

The suspected measles cases were reported through routine surveillance of the China Information System for Disease Control and Prevention, then confirmed by WHO case definition for measles (fever, generalized maculopapular rash, and cough, coryza, or conjunctivitis¹¹), which was also consistent with China’s national measles surveillance guidelines. The vaccination status of all cases was determined using their written vaccination history (the immunization certificate kept by the vaccine recipient, or the immunization record kept by the hospital where they worked), verbal reports were not accepted as documentation of immunity. Clinical information and lists of exposed contacts were obtained from a review of medical records and through case interview. Documented immunization records of identified contacts were reviewed as well. Contacts were informed about symptoms of measles and were instructed to contact any CDC if they would develop measles symptoms. Follow-up with nonimmune contacts was conducted again at the end of the incubation period to assure that contacts remained asymptomatic.

Laboratory testing

The initial serum samples of case 1 and case 2 were tested in the hospital where the two cases were diagnosed and reported. The measles laboratory of the hospital was one of the measles network laboratories in Beijing and certified by Beijing CDC. The subsequent serum tests of case 1 & case 2 and serum tests of case 3, as well as all viral tests, were performed in the laboratory at Beijing CDC, a WHO-accredited laboratory that attained a perfect score on WHO’s proficiency testing (PT) program in 2017.

Serum specimens collected 0–6 days from the rash onset were tested for measles-specific IgM; the subsequent serum specimens of case 1 and case 2 and serum specimens of case 3 were tested for measles IgG. Serology for measles-specific IgM and IgG was performed using commercial ELISA (Virion/SerionGmbH, Würzburg, Germany), in which the quantitative results of measles IgG were consistent with measles neutralizing antibody titers in plaque reduction neutralization (PRN) tests.^12,13 Seropositivity for measles IgG was defined as an IgG concentration ≥200 mIU/mL and seronegativity was defined as a concentration ≤150 mIU/mL.

Avidity of measles-specific IgG antibody was tested by modification of a commercial measles IgG ELISA (Euroimmun Medizinische Labordiagnostika AG, Germany).¹⁴ Relative avidity index (RAI) is used to judge the test results. Avidity is classified as low-avidity antibodies (RAI <40%), equivocal (RAI 40–60%), and high-avidity antibodies (RAI >60%); high avidity suggests past immunologic experience with measles through vaccination or natural measles infection.

Throat swabs were obtained for Measles virus RNA detected by using a real-time Reverse transcription polymerase chain reaction (RT-PCR) assay.¹⁵

Results

A total of three measles cases occurred between January 18 and 30 in 2018, including two healthcare workers on January 18 and 20 respectively and a contact of them on January 30.

Both case 1 and case 2 were the nurses of the biggest local children’s hospital in Beijing: one worked at Interventional Pulmonary Surgery and the other worked at Respiratory Ward. Workers of Interventional Pulmonary Surgery are responsible for interventional therapy of pulmonary and auxiliary diagnosis for children coming from other wards (mostly from Respiratory Ward). Therefore, co-exposure and contact probably exist between the two, but details were unknown. The two cases said they were not familiar with each other, so there had not been private contact between them after working hours.

There were no travels during the incubation period and no known sick contacts for the two cases. There were six outpatients reported as suspected measles in this hospital during the incubation period and two of them were confirmed by the laboratory. There were no suspected measles cases around the staff and the inpatients of the hospital. The index case was not ascertained through the outbreak review.

Both case 1 and case 2 developed a generalized rash and joint pain, without fever, cough, conjunctivitis, Koplik spots and other symptoms. Case 2 also developed a coryza. They all had documentation of receipt of one dose MCV in the past 5 years, but the MCV histories of their childhood were unknown.(Table 1)

Table 1.

Immunity history and clinical presentation for cases in a measles outbreak in Beijing, China, 2018.

			MCV immunization history			Clinical presentation
Case	Age, y	Sex	Doses received, number	Vaccination time, m/y	Vaccine type	Maximum temperature	Rash	Rash duration, d	Cough	Conjunctivitis	Koplik spots	Joint pain	Other
1	26	Male	1	4/2013	MV	36.8	Y	3	N	N	N	Y	N
2	24	Female	1	3/2015	MR	37.5	Y	5	N	N	N	Y	coryza
3	53	Female	0	-	-	38.2	Y	4	N	N	N	N	N

Abbreviations: MV, specification for measles vaccine, live; MR, measles and rubella combined vaccine, live.

One hundred and two exposed contacts aged between 20 and 53 years old were identified in their homes and workplaces during infectious period, of whom 22 (22%) had got measles ever, 31 (30%) had documentation of vaccination before exposure, 33 (32%) had received postexposure vaccination, 16 (16%) were not immune.

Subsequently, one additional case who was the mother of case 2 was identified among contacts. They lived together with close, long-term co-exposure in a badly ventilated environment (a bungalow less than 10 m² with one queen-size bed and a poor ventilation condition). She did not have a documented dose of MCV and also was not vaccinated after her daughter had been diagnosed measles because of the age limitation of the post-exposure vaccination. Case 3 presented with either rash and fever but without other symptoms or complications (Table 1).

An additional 15 contacts were identified who were all exposed to case 3 in a bank where she worked as a cleaner. None of the contacts had measles or vaccination before, so all contacts had received post-exposure vaccination. No more cases were identified among these contacts.

All cases were laboratory-confirmed with positive measles IgM results, which detected in serologic specimens collected from 0 to 6 days after rash onset (Table 2). Measles IgG was detected in one of the serum samples of each case collected on day 6, 4 and 1, respectively. Measles RT-PCR was negative from the pharyngeal specimen of each case, collected on day 6, 2 and 1, respectively. Both case 1 and case 2 had high-avidity IgG in follow-up serum samples (end-titer avidity index: 76.2% and 78.8%, respectively). (Table 2)

Table 2.

Laboratory results from serologic and virologic testing of cases in a measles outbreak in Beijing, China, 2018.

Case	Serum sample Number of days from rash onset to collection	IgM result	IgG result	IgG result(IU/L)	IgG avidity (etAI)	Days from rash onset to collection of throat swabs	RT-PCR
1	Serum 1:2d	Positive	Not done	Not done	Not done	6 d	Negative
	Serum 2:6d	Positive	Positive	2495.8	High (76.2%)
2	Serum 1:0d	Positive	Not done	Not done	Not done	2 d	Negative
	Serum 2:4d	Positive	Positive	5079.1	High (78.8%)
3	Serum 1:1d	Positive	Negative	79.7	Not done	1 d	Negative

Abbreviations: etAI, end-titer avidity index; IgG, immunoglobulin G; IgM, immunoglobulin M; RT-PCR, reverse transcription polymerase chain reaction.

Discussion

Evidence indicates that a single dose of correctly administered measles vaccine which results in seroconversion will afford lifelong protection for most healthy individuals.¹⁶ Nevertheless, this outbreak is a report of measles in people who had proved seroconversion evidence of vaccination, which indicates that secondary vaccine failure may still occur. In addition, one of the SVF measles case subsequently transmitted the virus to a contact, which indicates that the transmission by SVF can also occur. Although some outbreaks have been reported in which individuals with a history of MCV vaccination were confirmed with measles,^17–20 and some of them were positive for measles RNA by PCR which suggested they are potential sources of infection,¹⁷ the direct evidence of an SVF case being capable of transmitting to other individuals is rare. The outbreak in New York City in 2011 was the first documented outbreak in which an individual with SVF transmitted measles virus.⁹ To the best of our knowledge, this is the first report from China showing that an SVF measles case could transmit virus to others.

The time intervals since vaccination to one of the cases in Beijing were much shorter (within 5 years) than in New York City (15–24 years). Previous research^21,22 indicated that vaccine-induced antibodies will wane over time and lead to SVF when they are below protection level finally. Other studies have shown that persons with longer time since vaccination have slightly higher attack rates compared with those more recently vaccinated. However, time since immunization has seldom been reported to be a risk factor in field studies of measles outbreak.^23,24 Another reason for SVF may be gene as some studies concluded that genetic influences play a substantial role in the variation of antibody levels following immunization against measles.²⁵

Both case 1 and case 2 had a milder clinical reinfection without typical course of disease like fever, cough or 2–4 days of prodromal symptoms. That is consistent with previous outbreaks, in which symptomatic cases with measles that were later confirmed to have a secondary immune response, generally involved cases with mild clinical presentations.^26,27 Similarly, the two cases have been misdiagnosed until their measles screening laboratory results came out, albeit they had gone to a large-scale infectious disease hospital of Beijing. It was noteworthy that, in agreement of Mitchell’s findings,²⁸ none of the cases had Koplik spots, suggesting that Koplik spots are not necessarily seen in SVF measles cases.

The negative results of throat swab PCR for measles RNA of the two SVF cases may possibly be regarded as a result of the modified respiratory tract symptoms with a poor ability to transmit virus（decrease in quantity and duration of viral excretion). The reason of the transmission from case 2 to case 3 probably was the excessive close contact, long-term co-exposure in a badly ventilated environment. So it is supposed that the ability to transmit virus of SVF cases are limited, and infection may occur only in high intensity or continuous exposure.²⁹

There are limitations to our report: (1) Because the PRN test was not available in provincial measles laboratories in China, neutralizing antibody titers for each case were unable to be determined. Neutralizing antibody titers has the closest correlation with measles immunity and clinical protection, and it would not develop typical measles if pre-exposure PRN titer was greater than 120.³⁰ In another side, extremely high PRN titers in acute-phase serum from vaccinated persons with suspected measles infection might serve as a biomarker for SVF cases.³¹ Detection of measles IgG in our study was only a proxy for immunity and not absolutely equated with protection from the disease. (2) It is not possible to know about the quality of the vaccine they had received. Inappropriate storage conditions could alter the effectiveness of vaccines. It could not verificate the adequate respond of the cases or if they only achieved minimal titers following vaccination. But the laboratory results of high-avidity IgG antibody demonstrate that they had responded previously to measles virus and are secondary vaccine failures [9.31]. (3) None of the positive specimens of pathogens was obtained due to the modified clinical presentations or the timing of collection. Although all cases were confirmed by other laboratory results, the chain of virus transmission cannot be certain from the molecular biology prospective.

In conclusion, this is the second report of measles transmission from a vaccinated individual with documented secondary vaccine failure. Considering the existence of unforeseeable vaccine failures in highly vaccinated populations, the importance of herd immunity is emphasized in preventing transmission of this highly infectious disease.^9,32 Moreover, it is also important to note that the SVF cases with modified clinical presentations could easily be misdiagnosed, so it is critical to maintaining sensitive surveillance activities as well. This outbreak probably represents a series of rare events, and the SVF individuals in the transmission chain of measles are unlikely to threaten measles elimination yet,^9,17,32 further observations should be taken to justify a change in current measles control and elimination strategies.

Funding Statement

No outside funding was used to support this study.

Acknowledgments

We thank Haotian Zhang of the Dongcheng District CDC and Lu Zhang of the Xicheng District CDC and Tianwei Ma of the Haidian District CDC for conducting case and contact investigations.

Disclosure of potential conflicts of interest

All authors report no potential conflict of interest.