World health organization regional office for the western pacific regional guidelines

Annex 2: Rubella vaccine

Rubella vaccine is available on its own or in combination as measles-rubella vaccine (MR) and measles-mumps-rubella vaccine (MMR). The rubella vaccine strain that is most often used is the Wistar RA27/3 strain. The vaccine virus is cultured in human diploid cells

All these vaccines (as well as measles vaccines):

• 
  are freeze-dried live viruses, modified from the original virus so that ‘infection’ leads to immunity without causing illness or spread to contacts
  

• 
  come as a dry powder that can be frozen, but are generally stored at 2° to 8°C.
  
• 
  should be reconstituted only with the diluent supplied by the manufacturer and used within six hours of reconstitution
  
• 
  are sensitive to light as well as heat, especially when reconstituted
  
• 
  are usually given in the deltoid region of the upper arm as a dose of 0.5ml, by the subcutaneous or intramuscular route.
  

Vaccine effectiveness

A single dose of rubella vaccine induces an antibody response in 95-98% of recipients, and effectiveness in outbreaks has been between 90 and 97%. Even though antibody levels decline with time, there is no evidence that protection has declined – even after decades of follow-up.

A second dose will protect the small proportion who fail to be protected by the first dose.

Although the vaccine virus is excreted (mostly from the pharynx), there does not appear to be transmission to susceptible contacts.

Vaccine reactions

Vaccinees can develop mild rubella, including fever, sore throat, lymphadenopathy, rash, arthralgia and arthritis. Less than 1% of infants get mild rubella, but up to a quarter of adult women get joint symptoms (arthralgia or arthritis). Symptoms begin one to three weeks after immunisation and are usually only of short duration.

No major or long-lasting reactions are caused by rubella vaccine.

Although rubella vaccine virus is excreted following immunization, there are no reliable reports of vaccine viral transmission leading to infection of contacts.

Immunization in pregnancy

There is a small theoretical risk of rubella vaccine to a pregnant women leading to CRS. Therefore, rubella vaccine is contraindicated in pregnant women, and vaccinees are advised to avoid pregnancy for at least one month after immunization.

However, follow-up of women who were accidentally given rubella vaccine in pregnancy has not found a single case of the vaccine causing CRS. Therefore, rubella vaccine given in pregnancy is not a reason to consider termination of the pregnancy.

Immunization strategies

Experience in the Australia, United Kingdom, New Zealand, and other countries have shown that aiming for the individual protection of pregnant women is less effective as a control strategy than the prevention of rubella circulation by immunising both male and female children. This is because of the failure of many women to be vaccinated, as well as occasional vaccine failure.

Annex 3: CRS Surveillance

CRS surveillance is complex and requires human, laboratory, and financial resources. Therefore, it should be initially established in a limited area (a pilot) and evaluated before extending to national surveillance.

Establishing pilot CRS surveillance requires:

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  defined populations (selecting pilot site(s))
  
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  screening process (questions, signs & symptoms)
  
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  referral for clinical diagnosis
  
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  laboratory testing to confirm diagnosis
  
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  data collection (reporting) and analysis
  
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  evaluation of pilot.
  

Coordinator

Many people will need to be involved for surveillance to be effective. The coordinator will help all parts of the surveillance system to work well with each other. The coordinator can also ensure that all procedures and guidelines are in place where needed and provide oversight on the system and the day-to-day management of the data. The coordinator also ensures that adequate priority is given to establish the system.

Populations

1. 
   The surveillance will focus on one or more hospitals where most births occur and with the clinical and laboratory resources to undertake the surveillance. Usually, thousands of babies will need to be screened to provide an accurate estimate given the expected rate of CRS after a rubella epidemic is 1-4 per 1000 live births.
   
2. 
   Attendances at immunization visits under the age of one year provide another opportunity to identify cases of CRS. This is important as hearing loss will not usually be apparent at birth.
   

Screening

The first step is screening newborns and infants, using a standard procedure, to identify those who need further review so that a diagnosis (CRS or not) can be made.

The screening can consist of:

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  Asking mother for:
  

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  any history of fever and rash during the pregnancy
  
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  any suspicion of hearing loss or blindness/eye problems
  

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  Looking for:
  

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  hearing (heard turning to noise)
  
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  eye problem (white eyes / small eyes / large eyes / wobbly eyes)
  
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  heart disease (blue baby / hear murmur)
  
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  abnormal body (small head)
  

To enable screening to take place effectively requires:

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  training of the health workers to undertake the screening
  
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  system to ensure that every child in the target population (i.e., every birth or every child who attends for DTP3 or measles vaccine) is screened
  
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  system for referral and follow-up of every child who screens positive.
  

Clinical diagnosis

Every newborn or infant who tests positive needs to be referred to an experienced doctor who is able to diagnose CRS, using the established case definition (see Annex 4), modified as needed for local use.

The doctors who are able to do the clinical review need to be identified. It may be appropriate for doctors of different specialties to review the case depending on the kind of defect (e.g., ophthalmologist for any eye defect). A list of suitable doctors, identified by specialty and location, will assist the referral process. The doctors also need to agree to review the cases, which screen positive, and to follow a standard procedure and report on the cases referred to them.

Laboratory testing

The doctor will require laboratory testing (Rubella IgM antibody) to confirm a clinical diagnosis of rubella as well as for those cases where the diagnosis is uncertain. The capacity to take the blood from newborns and infants and for the laboratory to do the testing needs to be able to meet the extra demand.

Data management

A system for collecting the data on the number:

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  of children screened;
  
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  who screened positive;
  
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  clinically confirmed CRS; and
  
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  laboratory confirmed CRS.
  

Initially, this should be kept separate from the other disease reporting, but integration with AFP and other disease reporting can be planned for the future.

Evaluation

In addition to regular review of the programme, a formal evaluation after about six months of operation, is needed to follow-up on the pilot. Decisions made about rubella immunization and/or surveillance, including extending it, will influence the type of evaluation.

Additional strategies for estimating CRS disease burden

Additional strategies for identifying CRS disease burden:

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  identifying evidence of previous outbreaks and ongoing circulation.
  
• 
  analysis by year of birth of data from institutions from the blind and/or deaf to identify previous epidemics
  
• 
  population screening for rubella IgG to define the pattern of infection from which CRS burden can be estimated
  

Annex 4: Case Definitions

Rubella

Suspected rubella case

A suspected rubella case is any patient of any age in whom a health worker suspects rubella. A health worker should suspect rubella when the patient presents with:

(1) fever

(2) maculopapular rash, and one of the following:

(3) cervical, sub-occipital, or post-auricular adenopathy; or arthralgia/arthritis.

It will usually be difficult to distinguish rubella from measles, dengue, or a number of other febrile rash illnesses without laboratory testing.

Laboratory-confirmed rubella case

A laboratory-confirmed rubella case is a suspected case with a positive blood test for rubella-specific IgM (or other laboratory test) from a laboratory that is part of (or linked to) the Measles Laboratory Network.

Epidemiologically-confirmed rubella case

An epidemiologically-confirmed rubella case is a suspected case with contact/exposure to a laboratory-confirmed case of rubella during the 23 days before rash onset (maximum incubation period) while the source was infectious (one week before and after rash onset).

Rubella encephalitis

Suspected rubella encephalitis case

History of current or recent (14 days) rash-with-fever illness consistent with rubella AND seizures in person and/or acute confusional state (ACS) - in a person with no other identified cause of seizures or ACS (including no clinical or laboratory evidence of bacterial meningitis)

Laboratory-confirmed rubella encephalitis case

A suspected rubella encephalitis case with rubella IgM positive from CSF or viral dectection from CSF

Congenital Rubella Syndrome (CRS)

Suspected CRS case

A suspected case is any infant less than one year of age in whom a health worker suspects CRS. A health worker should suspect CRS when either

(1) there is a maternal history of suspected or confirmed rubella during pregnancy.

(2) the infant presents with heart disease, and/or suspicion of deafness, and/or one or more of the following eye signs: white pupil (cataract); diminished vision; pendular movement of the eyes (nystagmus); squint; smaller eye ball (micropthalmos); larger eye ball (congenital glaucoma).

Health workers should refer all suspected CRS cases to a qualified physician.

Clinically-confirmed CRS case

A clinically-confirmed case is one in which a qualified physician detects two of the complications in section (a) OR one from group (a) and one from group (b):

(a) Cataract(s) and/or congenital glaucoma; congenital heart disease; loss of hearing; pigmentary retinopathy.

(b) Purpura; splenomegaly; microcephaly; mental retardation; meningoencephalitis; radiolucent bone disease; jaundice with onset within 24 hours after birth.

Laboratory-confirmed CRS case

A laboratory-confirmed CRS case is an infant with a positive blood test for rubella IgM who has clinically-confirmed CRS.

Congenital rubella infection (CRI)

An infant with a positive blood test for rubella IgM who does not have clinically-confirmed CRS is classified as having congenital rubella infection (CRI).

Annex 5: New vaccine introduction (NVI) capacity indicators (DRAFT)

There are many vaccines that countries could add to their National Immunization Programme (NIP). To assist countries in deciding whether to introduce a new vaccine, WPRO prepared a booklet [Assessing New Vaccines for National Immunization Programmes. Manila: WHO, 2000].

An important issue is whether the investment for the new vaccine would be better spent on other improvements to the existing programme. These draft indicators can be used to assess capacity to introduce new vaccines. In this way, specific programme improvements can be made ahead of the introduction, to ensure that the new vaccine delivers its full potential benefit. It also provides a framework to help decide if investments are better made on first improving the routine programme.

It must be emphasised that the indicators are intended to help thinking and identify areas that may be of higher priority for a country than new vaccine introduction, and not categorical hurdles that countries need to ‘pass’ in all areas before they should consider new vaccine introduction.

1) obtaining full benefits from existing vaccines

a) national strategic plan and annual workplans for the NIP, with regular updating of all policies (safe injection, cold chain, immunization schedule)

b) 95% coverage for all vaccines; no district/lowest admin level with <90% [in general, this is the level to obtain the full benefits form a vaccine. It should not be construed that this level of coverage is an absolute before adding any other new vaccines.]

c) no gaps in immunity for existing vaccines (eg, for measles in older age groups)

d) Two dose measles schedule adopted (can have second dose implemented as regular campaign)

c) 95% coverage for timely (ie, within 24 hours) birth dose of HepB (timeliness may be defined differently for births outside hospital)

2) fully functional cold chain

a) National cold chain policy and management systems that includes a functional cold chain inventory that is used for vaccine stock management and planned placement, maintenance and replacement of equipment (including costing)

b) adequate for existing vaccine - at all levels; i.e., able to provide vaccines to the end-user at correct temperature; cold chain failure or freezing infrequent and causes addressed

c) able to meet any additional demands of the proposed new formulation

d) spare capacity to be able to meet campaign or unforeseen need

3) vaccine supply secure

a) 5-year forecasts for all existing vaccines (including any planned/likely campaigns)

b) appropriate levels of wastage (as defined by national programme)

c) no history of stock-outs at national or sub-national level

d) funding for existing vaccine secure over next 5 years

e) forecasts for new vaccine (including impact on existing vaccines) for new vaccine introduction and for next five years

f) funding adequate for new vaccine, and able to mobilise additional resources without impact on existing funding

4) immunization safety

a) all vaccines given with sterile needle and injection and placed in safety box without recapping

b) adequate disposal and destruction methods

c) capacity to procure, distribute, and dispose of additional injection materials for new vaccine, if needed

d) capacity to investigate and respond to adverse events following immunisation (AEFI)

5) surveillance

a) Timely, reliable, and comprehensive surveillance for existing EPI diseases

b) Surveillance with baseline data pre-introduction to monitor impact of new vaccine

6) establishing relative priority of new vaccine for health sector

a) assessment comparing disease burden (may be from local or other data) with costs of new vaccine introduction

Applying the NVI indicators for rubella vaccine

1) obtaining full benefits from existing vaccines

The priority for rubella is at least 80% coverage to prevent potential harm of increased adult susceptibility. Measles elimination has more stringent coverage requirement – at least 95% coverage, and countries should only consider rubella when they are moving towards measles elimination. The introduction of rubella as a wide-age range MR campaign can fill in any holes in measles immunity. As MR does not place any additional logistic challenges to the programme, the requirement to first get the full benefit is more relaxed, as adding MR can eb an opportunity to strengthen the rest of the programme.

2) fully functional cold chain

As MR places no additional demands on the cold-chain, there is no need for any special preparations for rubella. However, the introduction of rubella requires a wide age-range campaign and to implement it requires establishing a ‘surge’ capacity for the campaign. Thus, the whole cold chain, its functional status and capacity to meet the additional demands of the campaign will need to be reviewed. This review and any needed upgrades should increase the overall functionality of the cold chain for any future demands.

3) vaccine supply secure

Replacing measles with MR again requires no special calculations, but for many countries simply reducing wastage for all EPI vaccines can cover the additional cost of MR.

Ongoing funding for the additional cost of MR needs to be identified.
4) immunization safety

There will be no additional injection safety requirements except during the initial campaign. As this will ideally be a wide age-range campaign it will place considerable demands for the disposal of used injection material, as well as in relation to response to adverse events following immunisation (AEFI) (see Annex on AEFI in campaigns in Mealses guidelines)

As with the cold chain, preparing for the immunization safety for the campaign should have beneficial impacts for the ongoing routine programme. There is no additional challenge for immunization safety from using MR as compared with measles, except for vaccine reactions from the rubella component (joint pains).
5) surveillance

Adding rubella to the measles surveillance system should be straightforward and will provide new impetus for both. The issue of CRS surveillance is more complex, but needs to be initiated in at least one national hospital.

6) establishing relative priority of new vaccine for health sector

The additional cost of rubella vaccine is very small compared to the huge impact of a single CRS case. A formal cost benefit can still help decision-making, but will be based on assumptions unless there are good CRS data. As the average lifetime cost (to families as well as the government) of a case of CRS is likely to be over US$10,000, even if the incidence is at the lower bound of 1 per 10,000 births, rubella immunization is likely to be cost-saving for society.

From the perspective of countries like Australia and New Zealand where most cases of CRS are now born to mothers from other countries, and the lifetime health and disability costs to the Government alone are likely to be of the order of US$100,000 or more, there are also considerable interests in eliminating rubella in neighbouring countries, especially the Pacific island countries.

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