The hepatitis A vaccine HAVRIX, made by GlaxoSmithKline (GSK), has shown a number of possible side effects in pre-licensing clinical trials, ranging from mild to severe. These include local reactions such as heat, bruising, and swelling at the injection site, systemic symptoms such as headache, fever, and fatigue, as well as more serious conditions such as seizures and respiratory distress^[14].

Serious complications reported by GlaxoSmithKline (GSK) in the HAVRIX product insert during post-marketing surveillance of the vaccine included: rhinitis, vasculitis, hepatitis, jaundice, anaphylaxis and anaphylactoid reactions, serum sickness syndrome, thrombocytopenia, shortness of breath , dizziness, vasculitis, shortness of breath, multiple sclerosis, Guillain-Barre syndrome, musculoskeletal rigidity, injection site reaction, local swelling, paraesthesia, encephalopathy, syncope, myelitis, neuropathy, angioedema, erythema multiforme, hyperhidrosis, chills, symptoms flu-like and congenital anomaly.^[15]

The HAVRIX vaccine package insert reports that clinical trials of the vaccine have been conducted in over 37.000 individuals, however GSK provides very limited information about these studies in the vaccine package insert. The only study described in detail in the package insert, the HAVRIX 231 study, involved 1.241 healthy children aged 11 to 25 months.⁽¹⁶⁾ Safety studies in this clinical trial compared the health outcomes of individuals who received HAVRIX alone, HAVRIX in combination with MMR vaccine and Merck's chickenpox vaccine, or MMR and chickenpox vaccine followed by a dose of HAVRIX vaccine 42 days later. Solicited adverse events, such as fever, irritability, drowsiness, loss of appetite, redness, pain, and swelling, were recorded by parents on diary cards for 3 days following vaccination and were submitted to clinical study monitors. Parents of study participants collected information on unsolicited adverse events that occurred between days 4 and 31 after vaccination and followed up by telephone 6 months later. Although the vaccine package insert provides limited information on the health outcomes of the 1.241 study participants, additional data on this particular study was released in February 2013 as part of GSK's commitment to increase clinical transparency through public disclosure of vaccine reports. GSK Clinical Trials (CSR) on the GSK Clinical Trials Registry.^(17]

According to HAVRIX 231 clinical trial documents published by GSK in 2013, more than 62% of study participants who received HAVRIX alone, nearly 58% of study participants who received HAVRIX in combination with MMR and chickenpox vaccine, and more than 66% of participants who received MMR and chickenpox vaccine followed by HAVRIX on day 42 experienced an adverse reaction in the first 30 days following vaccination.(19) Of the 1.241 children who participated in this clinical trial, 51 , or 4 percent, experienced a serious adverse event following vaccination, with half of these serious reactions occurring in children who received HAVRIX in combination with the MMR and chickenpox vaccine.⁽¹⁹⁾

Details of the serious adverse events that occurred during HAVRIX study 231 remain unknown, as the information was redacted by GSK prior to publication. The document, however, reports that one serious adverse reaction, a diagnosis of autism following vaccination with HAVRIX in combination with the MMR and chickenpox vaccine, “was considered by the investigator to have a possible causal relationship to the vaccination.”^[20)

The HAVRIX Study 231 document released by GSK also highlighted that the diagnosis or suspicion of an immunodeficiency condition such as HIV or a newly diagnosed neurological disorder, in addition to other possible medical events occurring during the clinical study, would result in the removal of the individual's results from the final outcome of the study.⁽²¹⁾ 1.474 children were initially enrolled in the study; however, the final data include the outcomes of only 1.241 children. In the Study 231 document, GSK says that four children who suffered adverse events were removed from the study and that a further seven were eliminated for "other reasons", with further details GSK failing to provide.⁽²²⁾

TWINRIX⁽²³⁾

Adverse events reported during pre-licensing clinical trials of GlaxoSmithKline's (GSK) TWINRIX hepatitis A/hepatitis B vaccine include: redness, pain, hardness and swelling at the injection site, headache, fatigue, nausea, diarrhea, vomiting , upper respiratory tract infection, insomnia, anorexia, dizziness, migraine, paraesthesia, drowsiness, syncope, dizziness, muscle and joint pain, back pain, constipation, weakness, agitation, irritability, abdominal pain, influenza-like illness, erythema, petechiae, rash, sweating, urticaria, lymphadenopathy, dysgeusia, hypertonia, tingling, migraine, flushing, photophobia and hypotension.⁽²⁴⁾

Serious complications reported by GSK in the TWINRIX product insert during post-marketing surveillance of the vaccine have included: meningitis, herpes zoster, allergic reaction, anaphylactoid reaction, anaphylaxis, serum sickness syndrome days to weeks after vaccination (between including arthralgia/arthritis, fever, urticaria, erythema multiforme, ecchymosis and erythema nodosum) thrombocytopenia, thrombocytopenic purpura, Bell's palsy, convulsions, encephalitis, encephalopathy, Guillain-Barré syndrome, myelitis, multiple sclerosis, neuritis, neuropathy, optic neuritis, paralysis, paresis, transverse myelitis, hepatitis, jaundice, shortness of breath, bronchospasm, including asthma-like symptoms, conjunctivitis, visual disturbances, earache, tinnitus, palpitations, tachycardia, vasculitis, dyspepsia, arthritis, alopecia, eczema, erythema multiforme, erythema nodosum, hyperhidrosis, lichen planus and muscle weakness.⁽²⁵⁾

Pre-licensure clinical trials of TWINRIX, a bivalent vaccine combining HAVRIX (inactivated hepatitis A vaccine) and ENGERIX-B (recombinant hepatitis B vaccine), were limited to approximately 2.500 participants. In the United States, TWINRIX has been studied in only 773 healthy adults between the ages of 18 and 70. In this pre-clinical vaccine study, study participants received TWINRIX, one dose of HAVRIX (hepatitis A vaccine), one dose of ENGERIX-B (hepatitis B vaccine), or one dose of both HAVRIX that of ENGERIX-B. Adverse events such as fever, irritability and drowsiness, loss of appetite, redness, pain and swelling were actively solicited by the clinical study monitors only for 3 days following vaccination. Data on unsolicited adverse reactions were collected between days 4 and 31 after vaccine administration. GSK reports that data collected from US clinical trials is comparable to that reported from other clinical trials, but this data has not been published. Adverse events reported during prelicensure clinical trials included injection site redness, swelling, and hardness, agitation, insomnia, abdominal pain, vomiting, anorexia, respiratory tract infection, vertigo, dizziness, migraine, rash, weakness, and more Still.⁽²⁶⁾

In the comprehensive evidence assessment report, Adverse Effects of Vaccines: Evidence and Causality,⁽²⁷⁾ published in 2012 by the Institute of Medicine (IOM), evaluated eight adverse events reported following the hepatitis A vaccine.⁽²⁸⁾ These adverse events included acute disseminated encephalomyelitis, transverse myelitis, multiple sclerosis, Guillain Barre syndrome, chronic disseminated inflammatory polyneuropathy, Bell's palsy, anaphylaxis, and autoimmune hepatitis.

Of the eight vaccine-related adverse events evaluated, the IOM Committee concluded that the evidence for or against a causal relationship between the hepatitis A vaccine and all eight vaccine-related adverse events is inadequate, due to the total absence of methodologically valid published studies necessary to make a determination.^(29]

A study published in 2011 linked hepatitis A vaccination to Henoch-Schönlein purpura, a disorder that causes bleeding and swelling of small blood vessels.^(30] In 2012, an epidemiological study examining the risk of immune thrombocytopenic purpura (ITP), a blood disorder that causes unusually low levels of platelets in the body, following vaccination found significantly higher numbers of reported cases in individuals between the ages of 7 and 17 years following vaccination with the hepatitis A vaccine. The study authors recommended further research into this association, but no additional studies have been published.^(31]

Acute disseminated encephalomyelitis (ADEM) combined with acute motor axonal neuropathy following hepatitis A vaccine and infection with Campylobacter jejuni, a bacterium commonly associated with food poisoning, was documented in a case study published in 1999.⁽³²⁾ In 2009, doctors in Singapore reported a case of retrobulbar optic neuritis in an HIV-positive man following vaccination with the hepatitis A vaccine.^(33]