Rubella Vaccine: Changing the Course of a Once Common Childhood Illness

History

Rubella was initially thought to be a variant of measles or scarlet fever. It was only in 1814 that this disease was first classified as a separate illness in German-language medical literature.This is how rubella came to be known as “German measles” in English [3]. 

The term “rubella” was first used in English-language literature in 1866 after it was coined by Henry Veale. “Rubella” is derived from the Latin word “rubellus,” which means “little red” (a reference to the skin coloration caused by the disease). In 1914, Alfred F. Hess discovered that the causative agent of rubella was a virus. He made this determination after establishing that bacteria were not responsible for causing the illness. His observation was confirmed in 1938 by two Japanese scientists, Y. Hiro and S.Tasaka [1]. 

In 1941, Norman Gregg, an Australian ophthalmologist, was the first person to report the occurrence of congenital cataracts among infants born to women who contracted rubella during the first trimester of their pregnancies. It was the first time CRS was recognized as a distinct illness [1,3].

In 1962, there was a landmark development with regard to rubella. Paul D. Parkman and his colleagues, Thomas H. Weller and Franklin A. Neva, isolated the rubella virus for the first time [3]. This was significant because attenuated rubella virus vaccines were developed shortly after this discovery was made. Subsequently, CRS became a nationally notifiable disease in the US in 1966. Three years later, the first Rubella vaccine was invented by Stanley Plotkin, an American physician. It was  called RA27/3 [1,3].  

In 1971, the rubella vaccine was combined with the measles and mumps vaccines. The combined measles, mumps, and rubella (MMR) vaccine has been licensed for general use in the US ever since. In 2005, a varicella component was added to the MMR vaccine and licensed in the US. The MMRV vaccine has since become a standard tool in preventing four diseases that were once common among children [3]. 

WHO has encouraged all member countries to include rubella vaccines in their national immunization programs. In 2003, the Pan American Health Organization (PAHO)  set milestones for eradicating rubella in the Americas. In 2009, PAHO’s efforts were successful, and the Americas became the first and the only WHO region to eliminate rubella.

In 2005, the WHO European Region (EUR), which includes 53 member countries, became the second WHO region to set up a goal of eradicating rubella. Despite the fact that all member states have introduced rubella vaccinations into their national programs, this goal has not yet been achieved.

In 2012, The Western Pacific Region (WPR) of  WHO sped up its vaccination efforts to eliminate rubella as soon as possible. By 2015, all 36 member countries in the region had introduced RCVs into their national immunization programs. By 2019, vaccination coverage in the region had reached 96%. Australia, Brunei Darussalam, Macao (an administrative region of China), New Zealand, and the Republic of Korea successfully eliminated rubella. 

In 2013, the Southeast Asia region (SEAR) became the fourth WHO region to establish a goal of eliminating both rubella and CRS by 2020. By 2016, eight member countries introduced RCVs to their national immunization programs. In 2020, only the Maldives and Sri Lanka were verified to have achieved complete rubella elimination.

By 2019, three other countries, including India, Indonesia, and North Korea, also introduced RCVs into their national programs. These three countries accounted for around 84% of infants in the WHO SEAR region. As of 2020, Bangladesh, Bhutan, Nepal, Sri Lanka, Timor-Leste, Maldives, and Sri Lanka have been verified by WHO as being free of rubella.

Only 16 out of 22 member states of the WHO Eastern Mediterranean Region (EMR), including one geographical area, have introduced RCVs. In 2019, Iran, Bahrain, and Oman were verified to have eliminated Rubella. 

Countries belonging to the WHO African Region (AFR), including Cape Verde, Mauritius, and Seychelles, were the first in their region to introduce the rubella vaccine. Between 2012 and 2020, 28 more countries in the region introduced the vaccine even before they began childhood immunization programs.

As of 2020, 84 out of 195 WHO member countries have successfully eradicated rubella, and four more member states have set up rubella elimination goals. Additionally, 173 out of 195 (89%) member countries have included rubella in their immunization programs. But, as per the estimates provided by WHO, over 100,000 infants worldwide are born every year with CRS [4].

Epidemiology

Rubella occurs worldwide [3]. It is a seasonal disease with an especially high incidence during the spring. Large epidemics usually occur every three to eight years. Cases peak between March and June in countries in the Northern Hemisphere. In contrast, countries in the Southern Hemisphere see a rise in cases between August and December. However, there are exceptions. For instance, Peru and South Africa, countries that lie in the Southern Hemisphere, have slightly varying seasonal patterns. These two nations experience an increase in cases between May and October [5].

United States

The US witnessed a massive rubella outbreak between 1964 and 1965. During this epidemic, the country reported around 12.5 million cases of rubella. This particular epidemic caused 11,250 abortions, 2,100 neonatal deaths, and 2,000 cases of encephalitis. About 20,000 infants were born with congenital disabilities. The financial burden resulting from this epidemic was around $1.5 billion [6]. 

By 2004, rubella and CRS were successfully eliminated from the country. The nine CRS cases reported between 2004 and 2014 were either import-associated or from unknown sources [3].  

Eastern Mediterranean and African regions

The WHO EMR (Eastern Mediterranean Region) and AFR (African Region) still need to set regional goals to eliminate rubella and CRS. In the EMR region, Afghanistan, Pakistan, Djibouti, Sudan, and Somalia have no national immunization programs. 

Also, around 16 countries in Central and Western Africa are yet to introduce RCVs. As a result, the number of rubella cases in these countries has increased from 865 cases in 2000 to 11,787 cases in 2018 [4].

Europe

Though rubella was not completely eliminated in Europe, incidences gradually dropped as more and more countries included RCVs in their national immunization programs. The incidence in 2000 was 716.9 cases per 1,000,000 population, which accounted for 621,039 cases. In 2005, it decreased to 234.9 cases per 1,000,000 (206,359 cases). It dropped further to 0.67 cases per 1,000,000 population in 2019 (620 cases). Also, the number of CRS cases in the region decreased from 16 cases in 2005 to eight cases in 2019 [7]. 

Western Pacific Region

The incidence of rubella in the WHO WPR (Western Pacific Region), including China and Japan, has increased almost eight times from 2017 to 2019, which is 18.41 cases per 1,000,000 population. The outbreaks in China and Japan during this period accounted for 90% of all rubella cases worldwide. 

In China, around 30,000 cases were reported in 2019 alone. According to the data provided by the National Notifiable Disease Reporting System (NNDRS), students between 15 and 19 years were the most affected [5]. 

Japan has also witnessed a massive outbreak in the recent past. It began in 2018 and continued until the 13th week of 2020. In all, 5,296 cases were recorded [8]. It is the third massive outbreak in Japan since 2000. The first outbreak of the 21st century occurred in 2004. It consisted of 4,248 cases. 

The country witnessed a second massive outbreak between 2012 and 2014. A total of 12,614 cases were reported, and around 45 cases were infants born with severe disabilities [8]. Unvaccinated men between 35 and 51 years were the most affected. Most cases were reported in Tokyo and its neighboring communities [9].

How is it spread?

Humans are the only known hosts for the rubella virus [10]. It is contagious and can spread from one person to another. Viral shedding can start seven days before the initial appearance of rashes and continue for up to seven days after their onset. 

• Exposure to the respiratory droplets released into the air by an infected person while talking, coughing, or sneezing.
• Exposure of a fetus to the virus via its mother. (When a pregnant woman contracts the viral infection during the early phase of her pregnancy, there is a 90% chance of infecting her fetus [11].)
• Exposure to the bodily secretions of infants with CRS. (Infected infants shed large amounts of the virus through their body secretions during the first 12 months of their life [3].)

Biology of the disease

Once the rubella virus enters the human body via the respiratory route, it replicates in the nasopharyngeal mucosa (nasal cavity). It also spreads to the regional lymph nodes [1,3]. Eventually, the viral load increases, causing a systemic infection that affects the infected person’s bloodstream [1]. 

In pregnant women, the placenta gets infected when the virus is found in the bloodstream (viremia), causing a transplacental infection of the fetus. It can lead to fetal damage due to cell destruction and impaired cell division during the organ development phase. This results in congenital disabilities, including hearing loss, ocular damage, and cardiovascular abnormalities. It could also result in the death of the fetus [1,3].

Symptoms

The incubation period of the rubella virus is 12 – 23 days. The clinical presentation of the illness is usually mild, and about 25 – 50% of cases are asymptomatic. 

Rashes appear on the face after the end of the incubation period. They eventually spread to the trunk and other extremities within 24 hours and last for about three days. One to five days before the rashes appear, other symptoms may manifest, including:

• Low-grade fever
• Headache
• Malaise
• Mild conjunctivitis (redness or swelling of the eye)
• Lymphadenopathy (swollen lymph nodes)
• Sore throat
• Cough
• Rhinorrhoea (runny nose)

Rubella-related complications include:

• Joint pains (common in adult women).
• Arthritis (common in adult women).
• Thrombocytopenic purpura (a rare disorder [one in 3.000 cases] that forms clots in small blood vessels all over the body).
• Encephalitis (inflammation of the brain). It is rare, fatal, and occurs in approximately one in 6,000 cases [1,3].
• Pregnant women can have miscarriages and give birth to stillborn babies.
• Hearing impairment, congenital heart disease, developmental disorders, cataracts, glaucoma, and neonatal deaths in infants [1].

Diagnosis

The following diagnostic methods are used to confirm rubella infection:

• Real-time polymerase chain reaction (RT-PCR) – detection of rubella virus RNA.
• Viral culture – isolation of rubella virus in cell culture.
• Serologic Testing – detection of IgM and IgG antibodies from serum samples collected within the first few days following the onset of rashes.
• Virus sequencing – sequencing of nucleotides and comparing the resulting sequence with reference virus sequences that represent the rubella virus genotypes [1,3].
• Ultrasonography – Ultrasonography is performed on susceptible pregnant women to detect the RNA of the rubella virus in amniotic fluid for diagnostic confirmation and identify fetal abnormalities [1].

Treatment

There are no antiviral drugs available to treat rubella. In most cases, patients exhibit mild symptoms. They can be self-managed with proper rest and fever-reducing anti-inflammatory drugs.

Immunoglobulins can be administered intravenously in acute thrombocytopenia (abnormally low platelet levels). Anticonvulsants can be used to manage seizures in case of encephalitis [1].

Prevention

Rubella vaccines provide lifelong protection against rubella and CRS [1]. They are safe and effective, and nearly 95% of people who receive the first dose of the RCV develop immunity. Over 90% of those who have completed their first vaccination dose develop immunity against rubella for at least 15 years [3]. 

Rubella vaccines are available in both monovalent formulations and combinations with other vaccines. These include MR, MMR, and MMRV vaccines [10]. The Advisory Committee on Immunization Practices (ACIP), a committee within the US Centers for Disease Control and Prevention (CDC), recommends the MMR and MMRV vaccines.

• MMR vaccine: MMR vaccine is licensed to be administered to people 12 months or older. Children between 12 and 15 months should receive the first dose of the vaccine. The second dose is given if the individual has failed to generate an immune response following the first dose. It is usually administered when the child is four to six years old. The CDC recommends that the gap between the first and the second dose be at least four weeks. 
• MMRV vaccine: MMRV vaccine is licensed to be administered to children between 12 months and 12 years. It should not be administered to people who are 13 years or older. Children between 12 and 47 months should receive the first dose of the vaccine. For the second dose, each component of the MMRV vaccine is administered over separate injections. Also, people receiving the first dose of MMRV vaccines at age 48 months or older must receive each MMRV component separately over separate injections. The CDC recommends that the gap between the first and second doses be at least three months. However, an interval of four months is also accepted [3].

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