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WHAT'S NEW THIS SUNDAY: TWO ON MEASLES, ONE ON RUBELLA

Saturday, 15th of September 2012 Print
  • TWO ON MEASLES, ONE ON RUBELLA
  • EVALUATING MEASLES VACCINES: CAN WE ASSESS CELLULAR IMMUNITY?

Rory D de Vries and Rik L de Swart*

* Author for correspondence

 

 

Expert Review of Vaccines

July 2012, Vol. 11, No. 7, Pages 779-782 ,Bottom of Form


ABSTRACT

 

Measles remains an important cause of childhood mortality, and global eradication of the disease is being seriously considered. Because of limitations of the current live-attenuated vaccines, new vaccines and routes of administration are being investigated. In the article under review, the authors have measured measles-specific humoral and cellular immune responses after two doses of live-attenuated measles vaccine and found limited correlation between the two. This study highlights an important issue, namely that we cannot assume humoral and cellular immune responses to go hand in hand. However, it remains to be determined if assays with peripheral blood lymphocytes can be used as a correlate of protection from disease.

Live-attenuated measles virus (MV) vaccines were first introduced in the 1960s and have an impressive record of safety and effectiveness. Vaccination induces both humoral and cellular immunity, and high coverage in two-dose regimens has successfully interrupted endemic MV transmission in many geographic regions. MV-specific virus-neutralizing (VN) antibodies been identified as a correlate of protection from disease. However, several studies have suggested that cellular immune responses may also confer protection from measles in the absence of VN antibodies. Recently, Jacobson et al. measured humoral and cellular immune responses in a large cohort study of 764 subjects aged 11–22 years who had received two doses of measles-containing vaccine and demonstrated that the outcomes of these assays are not controlled or one only poorly correlated [1]. They concluded that specific humoral and cellular responses to measles vaccination are independent and suggested that both should be measured in clinical studies evaluating new measles vaccines or vaccination strategies.

VN antibody levels above 120–200 mIU/ml have been identified as a correlate of protection from measles in two independent studies [2,3]. Indeed, passive immunization with antibody preparations results in protection against measles, and maternal antibodies protect infants during the first months of life. In this respect, it is important to discriminate between protection from and clearance of MV: it is generally accepted that for the latter, cytotoxic T-cell responses are of crucial importance [4–6], as also illustrated by the fact that subjects with cellular immunodeficiency usually develop severe and often fatal disease after MV infection [7].

It has been demonstrated that some MV-vaccinated subjects with low VN antibody titers have detectable MV-specific T lymphocytes in their peripheral blood [8,9]. In addition, it was shown that MV-vaccinated subjects with undetectable MV-specific VN antibodies are still significantly protected from measles as compared with nonvaccinated subjects [3]. The incubation time of measles is relatively long, allowing the immune system to develop a secondary immune response. This may limit MV replication and restrict or completely prevent subsequent clinical disease [2,10,11].

In the study under review, the authors set out to reproduce their previous observations of an apparent independence between humoral and cellular immune responses to MV vaccination [12]. In comparison with their previous report, they now used a larger study cohort and improved immunological assays.


Summary of methods & results

 

Study cohort

The study cohort consisted of 764 individuals, and was a combination of two previously described cohorts [13,14]. The first included 388 healthy children (11–19 years) and the second one had 376 healthy children and young adults (11–22 years). All subjects had received two doses of measles vaccine, the first one at approximately 12 months and the second one at least 1 month after the first dose.

Humoral immune responses

In their previous study, the authors used MV IgG ELISA assays to assess antibody levels to measles. Here, MV-specific VN antibody levels were determined by using a plaque reduction microneutralization (PRMN) assay [15]. Briefly, serial dilutions of heat-inactivated serum were mixed with 20–60 plaque-forming units of recombinant MV expressing green fluorescent protein, incubated for 1 h at 37°C and subsequently plated with Vero cells in a 96-well plate. After 2 days, plaques were counted, 50% end point titers were determined and titers were converted to international units per milliliter using the Third International Standard for Anti-Measles.

Cellular immune responses

In their previous study, the authors used lymphocyte proliferation assays to assess cellular immunity to measles. In this study, they used an IFN-γ ELISPOT assay, for which they previously reported high accuracy and precision [16]. Briefly, peripheral blood mononuclear cells (PBMCs) were cultured in the presence or absence of live MV vaccine strain Edmonston B (multiplicity of infection: 0.5) or stimulated with phytohemagglutinin as positive control. After determining the optimal counting parameters, ELISPOT plates were analyzed automatically. In addition, the secretion of 12 different cytokines in the supernatants of MV-stimulated PBMCs was used as a secondary measure of cellular immunity. Results for seven cytokines (IL-2, IL-6, IL-10, IFN-α, IFN-γ, IFN-λ1 and TNF-α) were analyzed. IL-4, IL-5, IL-12, IL-13 and IL-17 were excluded, since the authors did not detect MV-specific production of these cytokines.

Study objective

As a primary objective, the authors assessed correlations between MV-specific humoral and cellular immune responses, testing their hypothesis that these responses following a second dose of measles-containing vaccine are independent.

Results

The authors report a median PRMN titer of 844 mIU/ml, and 68 subjects (8.9%) had antibody levels below the threshold for protection from disease. Furthermore, a median of 36 IFN-γ spot-forming cells per 2 × 105 PBMCs was detected. Using Spearman’s rank correlation test, the authors found only a weak and even a negative correlation between PRMN titers and IFN-γ ELISPOT counts. No quantitatively important correlations between PRMN titers and cytokine levels were observed. The only substantial correlations found were between cytokine levels: IL-2 levels were positively associated with IL-10 and IFN-γ, IL-10 with IFN-α and IFN-γ and IFN-α with IFN-λ1. Correlations did not change when controlling for demographic and clinical variables. Multiple linear regression analysis demonstrated that all markers for cellular immunity taken together were significantly associated with PRMN levels, but explained only 4.7% of the variability in the VN antibody titers. 

Discussion & significance of results

This study confirms previous observations that MV-specific antibody levels and T-cell responses detected in the peripheral blood of vaccinated subjects do not correlate. In their discussion, the authors recognize they cannot exclude that some individuals may have been exposed to wild-type MV. Furthermore, blood samples were collected months to years after the second vaccination, so results may have been clouded due to waning immunity. However, the large number of subjects included in the study, the statistical evaluation based on median rather than mean responses and the fact that the subjects resided in an area where virtually no measles cases were observed during the study period strongly suggest that their conclusions are justified. The authors also conclude that in future measles vaccination studies both humoral and cellular immune responses should be measured to demonstrate non-inferiority of candidate new vaccines or vaccination routes in comparison with the existing measles vaccines.

Although seemingly justified, some problems are associated with this statement. As described above, VN antibodies have clearly been identified as a correlate of protection against measles. Moreover, it is thought that VN assays measure the actual biological function of MV-specific antibodies: in subjects who carry protective levels of VN antibodies the virus is neutralized in vivo in a similar way as measured in the VN assay in vitro. Although it is generally accepted that cellular immunity indeed contributes to protection from measles [17], two crucial problems need to be solved:

 

• Can biological function of MV-specific memory T lymphocytes be measured?

 

• Is it possible to use PBMCs for this purpose?

IFN-γ ELISPOT assays can be reliably used to determine the frequency of MV-specific T cells in peripheral blood. However, measurement of the production of IFN-γ upon in vitro stimulation is not necessarily directly related to the function these cells exert in vivo. In order to generate an effective secondary immune response, clonal expansion of specific memory T lymphocytes is a probable first response upon exposure to MV. This response is actually mimicked in the ‘old-fashioned’ lymphoproliferation assays. In recent years, several assays have been developed to measure the capacity of virus-specific T lymphocytes to control virus replication or clear infected cells [6,18,19], but it remains to be determined if any of these assays indeed measure the postulated protective T-cell responses.

Another fundamental problem is that it is becoming increasingly clear that virus-specific memory lymphocytes may not circulate but rather reside in mucosal or peripheral tissues [20]. If these are the cells that confer protection in subjects vaccinated against measles with nondetectable VN antibody levels, it may not be possible to design functional assays using PBMCs as correlates of protection.

Five-year view

 we expect further development and standardization of assays for the measurement of MV-specific cellular immune responses. Most importantly, there is an urgent need to apply and validate these assays in measles outbreak studies; it may be possible to collect PBMCs from vaccinated infants before exposure during these studies. Such studies would be able to address the questions raised earlier.

 

Key issues

 

• Live-attenuated measles vaccines are safe and effective, and induce both humoral and cellular immune responses.

 

• Implementation of high vaccination coverage in a two-dose schedule has resulted in regional elimination of measles in many parts of the world.

 

• Measles virus (MV) is highly contagious, and drops in vaccination compliance quickly result in reintroduction of the virus leading to small or large measles outbreaks.

 

• MV-specific virus-neutralizing antibodies as measured by plaque reduction neutralization assays have been identified as a correlate of protection from measles.

 

• The contribution of cellular immune responses to long-term protection is poorly understood, but it has been demonstrated that vaccinated seronegative subjects can be protected from measles.

 

• Although cellular immune responses have been investigated in individuals who had recovered from acute measles, a study into the correlates of protection has never been performed.

 

• The study reviewed here confirms previous observations of the independence of MV-specific humoral and cellular immune responses after two doses of MV vaccine.

 

• Considering that memory T lymphocytes may reside in peripheral and/or mucosal tissues, it remains to be determined if cellular immunological correlates of protection from measles can ever be identified using peripheral blood lymphocytes.

 

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter discussed in the manuscript. This includes employment, consultancies, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this article.

 

References

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Jacobson​‌ RM, Ovsyannikova IG, Vierkant RA, Pankratz VS, Poland GA. Independence of measles-specific humoral and cellular immune responses to vaccination. Hum. Immunol.73,474–479(2012). [CrossRef] [CAS]

Chen​‌ RT, Markowitz LE, Albrecht P et al. Measles antibody: reevaluation of protective titers. J. Infect. Dis.162(5),1036–1042(1990). [CrossRef] [Medline] [CAS]

Samb​‌ B, Aaby P, Whittle HC et al. Serologic status and measles attack rates among vaccinated and unvaccinated children in rural Senegal. Pediatr. Infect. Dis. J.14(3),203–209(1995). [CrossRef] [CAS]

Permar​‌ SR, Moss WJ, Ryon JJ et al. Prolonged measles virus shedding in human immunodeficiency virus-infected children, detected by reverse transcriptase-polymerase chain reaction. J. Infect. Dis.183(4),532–538(2001). [CrossRef] [Medline] [CAS]

Permar​‌ SR, Klumpp SA, Mansfield KG et al. Role of CD8(+) lymphocytes in control and clearance of measles virus infection of rhesus monkeys. J. Virol.77(7),4396–4400(2003). [CrossRef] [CAS]

de Vries​‌ RD, Yüksel S, Osterhaus ADME, de Swart RL. Specific CD8(+) T-lymphocytes control dissemination of measles virus. Eur. J. Immunol.40(2),388–395(2010). [CrossRef] [CAS]

Permar​‌ SR, Griffin DE, Letvin NL. Immune containment and consequences of measles virus infection in healthy and immunocompromised individuals. Clin. Vaccine Immunol.13(4),437–443(2006). [CrossRef] [CAS]

Ward​‌ BJ, Boulianne N, Ratnam S, Guiot MC, Couillard M, De Serres G. Cellular immunity in measles vaccine failure: demonstration of measles antigen-specific lymphoproliferative responses despite limited serum antibody production after revaccination. J. Infect. Dis.172(6),1591–1595(1995). [CrossRef] [Medline] [CAS]

Bautista-López​‌ N, Ward BJ, Mills E, McCormick D, Martel N, Ratnam S. Development and durability of measles antigen-specific lymphoproliferative response after MMR vaccination. Vaccine18(14),1393–1401(2000). [CrossRef] [CAS]

10 

Muller​‌ CP, Huiss S, Schneider F. Secondary immune responses in parents of children with recent measles. Lancet348(9038),1379–1380(1996). [CrossRef] [Medline] [CAS]

11 

Helfand​‌ RF, Kim DK. Gary HE Jr et al. Nonclassic measles infections in an immune population exposed to measles during a college bus trip. J. Med. Virol.56(4),337–341(1998). [CrossRef] [CAS]

12 

Dhiman​‌ N, Ovsyannikova IG, Ryan JE et al. Correlations among measles virus-specific antibody, lymphoproliferation and Th1/Th2 cytokine responses following measles–mumps–rubella-II (MMR-II) vaccination. Clin. Exp. Immunol.142(3),498–504(2005). [CAS]

13 

Haralambieva​‌ IH, Ovsyannikova IG, Kennedy RB et al. Associations between single nucleotide polymorphisms and haplotypes in cytokine and cytokine receptor genes and immunity to measles vaccination. Vaccine29(45),7883–7895(2011). [CrossRef] [CAS]

14 

Ovsyannikova​‌ IG, Haralambieva IH, Vierkant RA, Pankratz VS, Jacobson RM, Poland GA. The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity. Hum. Genet.130(4),547–561(2011). [CrossRef] [CAS]

15 

Haralambieva​‌ IH, Ovsyannikova IG, Vierkant RA, Poland GA. Development of a novel efficient fluorescence-based plaque reduction microneutralization assay for measles virus immunity. Clin. Vaccine Immunol.15(7),1054–1059(2008). [CrossRef]

16 

Ryan​‌ JE, Ovsyannikova IG, Poland GA. Detection of measles virus-specific interferon-gamma-secreting T-cells by ELISPOT. Methods Mol. Biol.302,207–218(2005). [CAS]

17 

Amanna​‌ IJ, Slifka MK. Contributions of humoral and cellular immunity to vaccine-induced protection in humans. Virology411(2),206–215(2011). [CrossRef] [CAS]

18 

van Baalen​‌ CA, Gruters RA, Berkhoff EG, Osterhaus ADME, Rimmelzwaan GF. FATT-CTL assay for detection of antigen-specific cell-mediated cytotoxicity. Cytometry. A73(11),1058–1065(2008). [Medline]

19 

Kreijtz​‌ JHCM, de Mutsert G, van Baalen CA, Fouchier RAM, Osterhaus ADME, Rimmelzwaan GF. Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus. J. Virol.82(11),5161–5166(2008). [CrossRef] [Medline] [CAS]

20 

Sheridan​‌ BS, Lefrançois L. Regional and mucosal memory T cells. Nat. Immunol.12(6),485–491(2011). [CrossRef] [CAS]

Affiliations

Rory D de Vries

Department of Virology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands

Rik L de Swart

Department of Virology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. r.deswart@erasmusmc.nl

 

  • A report on the large measles outbreak in Lyon, France, 2010 to 2011

Eurosurveillance, Volume 17, Issue 36, 06 September 2012

Surveillance and outbreak reports

Abstract and conclusions are below; full text is at http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20264 

In 2010 and 2011, the city of Lyon, located in the Rhône-Alpes region (France), has experienced one of the highest incidences of measles in Europe. We describe a measles outbreak in the Lyon area, where cases were diagnosed at Lyon University hospitals (LUH) between 2010 and mid-2011. Data were collected from the mandatory notification system of the regional public health agency, and from the virology department of the LUH. All patients and healthcare workers who had contracted measles were included. Overall, 407 cases were diagnosed, with children of less than one year of age accounting for the highest proportion (n=129, 32%), followed by individuals between 17 and 29 years-old (n=126, 31%). Of the total cases, 72 (18%) had complications. The proportions of patients and healthcare workers who were not immune to measles were higher among those aged up to 30 years. Consequently, women of childbearing age constituted a specific population at high risk to contract measles and during this outbreak, 13 cases of measles, seven under 30 years-old, were identified among pregnant women. This study highlights the importance of being vaccinated with two doses of measles vaccine, the only measure which could prevent and allow elimination of the disease.

. . .

Discussion and conclusion

It was estimated in 2009 that eight percent of people aged between six and 29 years were not immunised against measles in France [12]. The coverage is under the threshold of 95% needed for measles elimination [13]. The objective of this study was to describe the measles outbreak which occurred in Lyon, located in the Rhône-Alpes area, from 2010 to mid 2011. Our analysis focused on patients diagnosed with measles in LUH, pregnant women and HCW, and on virology and immunology data from the hospital virology-based surveillance. Overall, 407 cases of measles were diagnosed in LUH. According to 2009 estimations 92 percent of individuals between six and 29 years-old were immunised in France [12]. Moreover,  in 2010–2011, the vaccination coverage for measles at 24 months-old (1 dose) was 88.8% in the Rhône-Alpes region [11]. Consequently, IgG seropositivity rates among children and young adults under 30 years-old in the Rhone-Alpes region but also nationwide are likely to reflect more vaccination coverage than contact with the virus. Although the tested population was a biased sample of the Lyon population, seroprevalence of IgG against measles was low, especially in patients and HCW under 30 years. Vaccination against measles is recommended but not mandatory for HCW in France. Their risk to contract measles appears to be much higher than the general population and they can potentially transmit the disease to their patients, especially the immunocompromised ones [14]. It appears urgent to reach a higher vaccination coverage with two doses in the French population. Eliminating measles is one of the World Health Organization’s goal, which is expected for 2015 [15]. According to the results of our study, overall 78% of the measles cases were not vaccinated. A report based on French mandatory notifications between January 2008 and April 2011 [2] found similar rates concerning lack of vaccination: 86% of the cases did not receive the measles, mumps, and rubella (MMR) vaccine against measles, with differential compliance and immunisation coverage in the various districts of France. It pointed out that communications towards the general population about the need to be vaccinated in order to be protected, have to be strengthened.

Attention must be paid to newborns under one year of age because they are too young to be vaccinated and may no longer be protected by maternal antibodies. At the age of six months, 90% of the infants are not protected, irrespective of the mother’s immunisation status [16]. Measles acquired during pregnancy can have deleterious effect on the mother and child outcome [17]. The most serious and frequent complication reported for pregnant women is pneumonia [17-20]. The hospitalisation and case fatality rates among pregnant women may be higher than among non-pregnant adults [20]. Concordant with these data, four cases of pneumonia among 13 pregnant cases were found in our study. Six of the pregnant women were hospitalised. An increased risk of foetal and neonatal loss is also reported [17-20]. In one case observed in this study, a premature birth occurred, however it could have been attributable to other causes. Some authors also reported an increased risk of subacute sclerosing panencephalitis following neonate [21] or congenital [22] measles infection. Women in childbearing age should be informed of the risk of contracting measles and its possible complications. Vaccination that can only assure protection should be proposed as soon as possible in pre- or post-partum. Measles among pregnant women should be no longer considered uncommon in the regions that report outbreaks and should be systematically considered in the context of pregnant women presenting to a health practitioner with pneumonia. 

In comparison with other European countries, France has been the most affected with 13,957 cases reported between January and August 2011 [9]. Italy, who reported 4,300 measles cases during the same period was the second most affected European country [6]. Four measles cases among pregnant women were reported [6] and 36% of cases were hospitalised. Overall 14% presented complications [6], which was in concordance with the complication rate of 18% in the Lyon area. Romania also experienced a large measles outbreak in 2011, with 2,072 reported cases [8]. The complication rate in Romania was much higher than in the Lyon area (respectively, 39% and 18%). Finally, the Geneva canton in Switzerland, which neighbours the Rhône-Alpes region, only reported 41 measles cases between January and May 2011, so it was far less affected than Rhône-Alpes area [5]. There, serious control measures, with quarantining and a vaccination campaign were systematically implemented. The larger number of cases that we experimented during the outbreak in Lyon area did not prevent carrying out a vaccination campaign, however, quarantining each measles case was more difficult to implement.

The main limitation of our study was a possible underestimation of the true measles incidence, as, in France, about 50% of measles cases were not reported on mandatory notification [10]. However this should not bias time-trends. Moreover, we were unable to calculate its incidence per 1,000 inhabitants because the exact origin of individuals was not known.

In conclusion, catch-up vaccination campaigns should focus on individuals aged under 30 years-old who have not received two doses of measles vaccine and on HCW. The outbreak is likely to re-occur, especially in the regions of France with low vaccine coverage. Clusters of susceptible individuals accrued over the years [10,11]. Indeed, the French Institute for Public Health Surveillance (InVS) reported that among children of 24 months old in 2008, only 90% had received one dose of the measles vaccine while according to the French vaccination programme, they should have already got two doses [23]. A fourth epidemic wave has to be expected in France and Europe. Hospital-based surveillance of measles is relevant to estimate the spread of the disease in the community and to help with early detection of healthcare-acquired cases.

Acknowledgements
We thank the Agence Régionale de Santé de Rhône-Alpes (AM McKenzie, G Courbis) for their contribution to our surveillance of measles cases at Lyon University Hospitals. We thank F Champion, A Fichez, S Blanc, K Bellemin, C Volckmann, A Duvermy, MA Denis, P Nargues, JB Fassier, for their contribution to the hospitalised-based surveillance of measles cases. Manuscript editing by Ovid Da Silva is acknowledged.


References

  1. Haut Conseil de la santé publique (HCSP). Avis relatif à l’actualisation des recommandations vaccinales contre la rougeole pour les adultes. 11 février 2011. [Notice on update of recommendations for measles vaccinations in adults]. Paris: HCSP; 11 Feb 2011. French.
  2. Baudon C, Parent du Châtelet I, Antona D, Freymuth F, Poujol I, Maine C, et al. Caractéristiques de l’épidémie de rougeole démarrée en France depuis 2008 : bilan des déclarations obligatoires pour les cas survenus jusqu’au 30 avril 2011. [Characteristics of the measles epidemic in France which began in 2008: a review of mandatory reporting for cases occuring until 30 April 2011]. Bull Epidémiol Hebd. 2011;33-34:353-8. French.
  3. Benkimoun P. Outbreak of measles in France shows no signs of abating. BMJ. 2011;342:d3161.
  4. Six C, Blanes de CJ, Duponchel J, Lafont E, Decoppet A, Travanut M, et al. Spotlight on measles 2010: Measles outbreak in the Provence-Alpes-Cote d'Azur region, France, January to November 2010 - substantial underreporting of cases. Euro Surveill. 2010;15(50):pii=19754. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19754
  5. Delaporte E, Richard JL, Wyler Lazarevic CA, Lacour O, Girard M, Ginet C, et al. Ongoing measles outbreak, Geneva, Switzerland, January to March 2011. Euro Surveill. 2011;16(10):pii=19815. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19815
  6. Filia A, Tavilla A, Bella A, Magurano F, Ansaldi F, Chironna M, et al. Measles in Italy, July 2009 to September 2010. Euro Surveill. 2011;16(29):pii=19925. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19925
  7. Sabbe M, Hue D, Hutse V, Goubau P. Measles resurgence in Belgium from January to mid-April 2011: a preliminary report. Euro Surveill. 2011;16(16):pii=19848. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19848
  8. Stanescu A, Janta D, Lupulescu E, Necula G, Lazar M, Molnar G, et al. Ongoing measles outbreak in Romania, 2011. Euro Surveill. 2011;16(31):pii=19932. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19932
  9. European Centre for Disease Prevention and Control (ECDC).Surveillance report. European monthly measles monitoring. Stockholm: ECDC. Sep 2011. Available from: http://ecdc.europa.eu/en/publications/Publications/111018_EMMO_SEPT_2011.pdf
  10. Parent du Châtelet I, Antona D, Freymuth F, Muscat M, Halftermeyer-Zhou F, Maine C, et al. Spotlight on measles 2010: update on the ongoing measles outbreak in France, 2008-2010. Euro Surveill. 2010;15(36):pii=19656. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19656
  11. Dennetiere G, Fort B. Rougeole en Rhône-Alpes. Point sur la vague épidémique d’octobre 2010 à septembre 2011. [Measles in Rhône-Alpes. Sum up on the situation regarding the epidemic wave from October 2010 to September 2011]. Bulletin de veille sanitaire Rhône-Alpes. Numero special rougeole. 14 Nov 20122. French. Available from: http://www.invs.sante.fr/Publications-et-outils/Bulletin-de-veille-sanitaire/Tous-les-numeros/Rhone-Alpes/Bulletin-de-veille-sanitaire-Rhone-Alpes.-Numero-special-rougeole
  12. Lepoutre A, Antona D, Fonteneau L, Baudon C, Halftermeyer-Zhou F, Le Strat Y, et al. Enquête nationale de séroprévalence des maladies infectieuses 2009-2010, 1er résultats. Communication orale, 12ème Journées Nationales d’Infectiologie, Toulouse 2011. [National seroprevalence survey of infectious diseases 2009-2010, the first results. Oral communication, 12th National Symposium on Infectious Diseases, Toulouse 2011]. Med Mal Inf. 2011;41(6):suppl.1. French.
  13. Centers for Disease Control and Prevention (CDC). Increased transmission and outbreaks of measles — European Region, 2011. MMWR Morb Mortal Wkly Rep. 2011;60(47):1605-10.
  14. Botelho-Nevers E, Cassir N, Minodier P, Laporte R, Gautret P, Badiaga S, et al. Measles among healthcare workers: a potential for nosocomial outbreaks. Euro Surveill. 2011;16(2):pii=19764. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19764
  15. World Health Organization (WHO) – Regional office for Europe. Eliminating measles and rubella. Framework for the verification process in the WHO European Region. 2012. WHO Regional Office for Europe: Copenhagen; 2012. Available from: http://www.euro.who.int/__data/assets/pdf_file/0003/158304/EURO_MR_Elimin_Verification_Processv2.pdf
  16. Gagneur A, Pinquier D. Letter to the editor. Spotlight on measles 2010: timely administration of the first dose of measles vaccine in the context of an ongoing measles outbreak in France. Euro Surveill. 2010;15(41):pii=19689. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19689
  17. Manikkavasagan G, Ramsay M. The rationale for the use of measles post-exposure prophylaxis in pregnant women: a review. J Obstet Gynaecol. 2009;29(7):572-5.
  18. Ali ME, Albar HM. Measles in pregnancy: maternal morbidity and perinatal outcome. Int J Gynaecol Obstet. 1997;59(2):109-13.
  19. Chiba ME, Saito M, Suzuki N, Honda Y, Yaegashi N. Measles infection in pregnancy. J Infect. 2003;47(1):40-4.
  20. Eberhart-Phillips JE, Frederick PD, Baron RC, Mascola L. Measles in pregnancy: a descriptive study of 58 cases. Obstet Gynecol. 1993;82(5):797-801.
  21. Sawaishi Y, Abe T, Yano T, Ishikawa K, Takada G. SSPE following neonatal measles infection. Pediatr Neurol. 1999;20(1):63-5.
  22. Cruzado D, Masserey-Spicher V, Roux L, Delavelle J, Picard F, Haenggeli CA. Early onset and rapidly progressive subacute sclerosing panencephalitis after congenital measles infection. Eur J Pediatr. 2002;161(8):438-41.
  23. Institut de Veille Sanitaire (InVS). Couverture vaccinale rougeole: La couverture vaccinale à 24 mois. [Measles vaccination coverage among infants aged 24 months-old]. Paris: InVS. 13 Apr 2010. French. Available from: http://www.invs.sante.fr/Dossiers-thematiques/Maladies-infectieuses/Maladies-a-declaration-obligatoire/Rougeole/Couverture-vaccinale-rougeole

 

  • RUBELLA VACCINATION: MUST NOT BE BUSINESS AS USUAL

Correspondence

www.thelancet.com Vol 380 July 21, 2012; best viewed at www.thelancet.com 

The GAVI Alliance has announced support for eligible countries to introduce measles-rubella vaccine in their routine infant programmes and to start measles-rubella vaccine campaigns in children aged 9 months to 14 years. 30 countries are expected to have done so by 2015.1

Control programmes for congenital rubella syndrome need to consider features that affect rubella transmission rates and thus the risk of infection during pregnancy.2 These include: variation in vaccination coverage within and between countries; birth rate (at high birth rates, coverage well above 80% might be needed to avoid increasing the prevalence of susceptible adult women); and population isolation (local rubella extinction increases the mean age of infection in epidemics after rubella’s eventual reintroduction).2 The introduction of new and underused vaccines is affected by a country’s interest and its ability to obtain GAVI support (determined by gross national income and estimated coverage of three doses of diphtheria, tetanus, and pertussis vaccine) or other finance. Although the new global measles and rubella strategic plan3 encourages all countries to aim for control of congenital rubella syndrome and measles elimination, countries that receive GAVI funding might be quicker to introduce rubella containing vaccine than those that do not receive such funding. Since GAVIeligible and non-eligible countries and those with high and low coverage border each other, the usual process for introduction of new and underused vaccines will increase heterogeneities in rubella transmission across national boundaries. Countries that implement campaigns will strikingly reduce transmission in those younger than 15 years in the short term. This outcome will potentially increase the average age at infection in border areas of a neighbouring, nonvaccinating country, while currently susceptible adults will risk infection through travel to non-vaccinating countries or via imported cases. Vaccination of adolescent or adult women, part of successful congenital rubella syndrome control and elimination strategies,4 is not included in current plans. The unprotected population in the vaccinating country will build up again owing to pockets of low immunisation coverage in infants unless active measures are taken to reduce historical inequities. Large measles outbreaks with a significant increase in the average age of infection have occurred in many countries that had apparently achieved measles control, owing in part to suboptimum implementation of programme strategies.5 Such an occurrence for rubella, made more likely if the introduction of rubella containing vaccine occurs piecemeal, could decrease public confidence in immunisation even if the cumulative burden of congenital rubella syndrome is reduced.

Support for rubella-containing vaccine should not be “business as usual” at a time when multiple new vaccines are being introduced. Strong, sustained regional programmes that span countries of all income groups and specifically address rubella epidemiology are required to achieve the desired results.

This work was funded by the Bill & Melinda Gates Foundation. We declare that we have no conflicts of interest.

*F T Cutts, C J E Metcalf, J Lessler, B T Grenfell

felicity.cutts@wanadoo.fr

201 Boulevard Louis Bernard, 83250 La Londe les Maures, France (FTC); Department of Zoology, Oxford University, Oxford, UK (CJEM); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (JL); and Department of Ecology and Evolutionary Biology, Eno Hall, Princeton University, Princeton, NJ, USA (BTG)

 

1 Burki T. GAVI Alliance to roll out rubella vaccine. Lancet Infect Dis 2012; 12: 15–16.

2 Metcalf CJE, Lessler J, Klepac P, Cutts F, Grenfell BT. Minimum levels of coverage needed for rubella vaccination: impact of local demography, seasonality and population heterogeneity. Epidemiol Infect 2012; 16: 1–12.

3 WHO. Global measles and rubella strategic plan: 2012–2020. http://www.who.int/

immunization/newsroom/Measles_Rubella_StrategicPlan_2012_2020.pdf (accessed

April 30, 2012).

4 WHO. Rubella vaccines: WHO position paper. Wkly Epidemiol Rec 2011; 86: 301–16.

5 Centers for Disease Control and Prevention. Measles outbreaks and progress toward measles preelimination—African region, 2009–2010. MMWR Morb Mortal Wkly Rep 2011; 60: 374–78.

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