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Norovirus Vaccine Phase 2 Trial, Explained

Lambert Peng is a medical blog writer with a background in pharmaceuticals.

Introduction

In 2020, researchers published the results of a phase II clinical trial of a norovirus vaccine. This article uses plain language to describe what happened in that trial. I have also added some of my own commentary at the end.

Why was this study done?

Norovirus is a virus that causes severe nausea, vomiting, and diarrhea, even in healthy people. Every year, it causes over 200,000 deaths worldwide. It is commonly called the “stomach flu” or “stomach bug.” Norovirus infections spread very quickly among people who live close together with other people, such as those in healthcare facilities, nursing homes, college dorms, cruise ships, and military settings.

There are many different genetic variants of norovirus. If someone is immune to one variant, it does not always mean that he or she will be immune to another. Some variants are more common than others. The two most common norovirus variants that infect people are GI.1 and GII.4.

There is currently no vaccine available to prevent norovirus infections. In this study, researchers tested a new vaccine called TAK-214. TAK-214 contains ingredients that imitate the GI.1 and GII.4 variants of norovirus, so that the body will be tricked into thinking it is being invaded by those variants. The vaccine does not contain any live norovirus. Because it is still being tested, TAK-214 has not yet been approved for use by the general public.

The main purpose of this study was to find out how well TAK-214 works to prevent acute gastroenteritis, compared to placebo. “Acute gastroenteritis” is the medical term for nausea, vomiting, or diarrhea. A placebo is an injection that looks just like the vaccine, but doesn’t have any vaccine in it.

What happened during the study?

This study compared 2 groups of patients who received one injection of one the following:

  • TAK-214
  • Placebo

Patients were assigned to each group by chance alone. This is known as a “randomized” study. This was done to make the groups more similar, which makes comparing the groups more fair.

The patients and researchers did not know who received TAK-214 and who received placebo. This is known as a “blinded” study. This was done to make sure the results of the study could not be unfairly influenced by anyone.

All patients volunteered for the study. The volunteers were healthy male and female US Navy recruits aged 18-49 years old who were enrolled at the US Navy Recruit Training Command, in Great Lakes, Illinois.

Not all volunteers were able to participate in the study. The reasons for a patient not being able to participate in the study included:

  • Having any instance of acute gastroenteritis within 14 days of enrollment
  • Having fever, as defined by a body temperature greater than 38°C (100.4°F), within 3 days of enrollment
  • Having a weak immune system
  • Receiving any medication or treatment within the last 3 months that weakened the immune system
  • Being allergic to any ingredient in the vaccine
  • Being pregnant

The researchers kept track of the patients, starting from day 7 from the day they received their injection, until day 45. They started at day 7 because vaccines typically take several days to start working. They did not go past day 45 because that was when the recruits finished their training and got discharged.

The researchers kept track of how many times the patients had any instance of acute gastroenteritis. “Acute gastroenteritis” was strictly defined as being one or both of the following:

  • Having 1 or more episodes of vomiting (not caused by recruit training) within 24 hours
  • Having 1 or more unformed stools (diarrhea) within 24 hours

The researchers also classified how severe a patient’s acute gastroenteritis was. “Moderate” acute gastroenteritis was defined as one or both of the following:

  • Having 3 to 5 episodes of vomiting within 24 hours
  • Having 4 to 5 unformed stools within 24 hours

“Severe” acute gastroenteritis was defined as one or more of the following:

  • Having 6 or more episodes of vomiting within 24 hours
  • Having 6 or more unformed stools within 24 hours
  • Being admitted to the hospital
  • Requiring intravenous (injected) fluids for hydration due to acute gastroenteritis
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Any time a patient had an instance of acute gastroenteritis, he or she was expected to collect samples of the stool or vomit to be tested in a laboratory. The samples were tested to see if they contained any norovirus, and if so, which genetic variant of norovirus it was. That way, the researchers could be sure that the acute gastroenteritis was caused by norovirus, and not by a different bug or disease.

The researchers also collected blood samples from the first 200 patients who enrolled. A blood sample was collected right before each patient received his or her injection of either TAK-214 or placebo. Blood samples were also collected on day 8, day 29, and day 45. If any patient had an instance of acute gastroenteritis, a blood sample was also collected between day 7 and 14 from the time the acute gastroenteritis happened.

The study began on June 14, 2016 and ended on June 16, 2018. The researchers had originally planned for the study to last 1 year, but ended up making it into 2 years, because not enough patients in the first year had an instance of acute gastroenteritis. When there are not enough patients to study, researchers cannot collect enough information to make a good study.

What were the results of the study?

Researchers asked the question: Does TAK-214 protect people against acute gastroenteritis caused by the GI.1 and/or GII.4 variants of norovirus? To answer that question, they considered the following:

  • In the placebo group, 2087 patients finished the study. In that group, 142 patients had an instance of acute gastroenteritis between day 7 and 45. When the researchers tested their stool or vomit samples, they found 29 samples with norovirus. Of those cases, 26 patients had “moderate” or “severe” acute gastroenteritis, and 22 patients had to be “confined to quarters” (quarantined).
  • In the TAK-214 group, 2089 patients finished the study. In that group, 125 patients had an instance of acute gastroenteritis between day 7 and 45. When the researchers tested their stool or vomit samples, they found 19 samples with norovirus. Of those cases, 10 patients had “moderate” or “severe” acute gastroenteritis, and 9 patients had to be “confined to quarters.”
  • 0 samples in the placebo group and 1 sample in the TAK-214 group had the GI.1 variant.
  • 5 samples in the placebo group and 1 sample in the TAK-214 group had the GII.4 variant.

Because too few samples contained the GI.1 or GII.4 variant, the researchers could not confirm or deny that TAK-214 protects people against acute gastroenteritis caused by the GI.1 or GII.4 variant.

Researchers then asked the next question: Does TAK-214 protect people against acute gastroenteritis in general? After considering the data above, they calculated that TAK-214 is indeed 61.8% effective at protecting people against acute gastroenteritis in general. They also figured out that if a person does get acute gastroenteritis, being vaccinated with TAK-214 makes the acute gastroenteritis less severe.

The researchers also discovered that there were 24 samples in the placebo group and 15 samples in the TAK-214 group that had a different genetic variant: the GII.2 variant. Even though GII.2 is not one of the variants covered by TAK-214, it is still possible for the vaccine to protect against it, because of something called “cross-protection.” This means that even though a vaccine might be designed for a specific variant, it can actually help protect against different, but similar, variants. The researchers calculated that TAK-214 is 57.4% effective at protecting people against acute gastroenteritis caused by the GII.2 variant.

The blood samples that were collected on days 1, 8, 29, and 45 were also tested. Researchers tested the blood samples to see if they contained something called “histo-blood group antigen (HBGA)-blocking antibodies,” as well as something called “pan-immunoglobulins” (pan-Ig). HBGA-blocking antibodies and pan-Ig are molecules in the body that let researchers know whether a person might be immune to the norovirus. This is what the researchers found:

  • Patients who received TAK-214 were more likely to test positive for HBGA-blocking antibodies and pan-Ig compared to patients who received placebo.
  • In the TAK-214 group, going from day 1 to day 8, the number of patients who tested positive increased over time. The amount of HBGA-blocking antibodies and pan-Ig in their blood increased very rapidly.
  • In the TAK-214 group, going from day 8 to day 45, the number of patients who tested positive decreased over time. The amount of HBGA-blocking antibodies and pan-Ig in their blood decreased very slowly.
  • In the placebo group, patients who had an instance of acute gastroenteritis were more likely to test positive for HBGA-blocking antibodies and pan-Ig compared to patients who never had acute gastroenteritis.
  • In the placebo group, among patients who never had an instance of acute gastroenteritis, the number of patients who tested positive did not increase over time.

Were there any side effects?

The researchers watched every single patient who received an injection of either placebo or TAK-214 for 15 minutes afterward. They also kept track of any side effects the patients had for up to 28 days afterward.

The researchers looked at whether there were any “local” reactions to the vaccine. A local reaction is a side effect that is seen at the site where the vaccine was given, and can include pain at the vaccination site, redness, and/or swelling. In total, 71 patients in the placebo group and 93 patients in the TAK-214 group had a local reaction. Every single case was mild to moderate pain that lasted about 2 days, except for one case of “severe” pain in the placebo group.

The researchers also looked at whether there were any “systemic” reactions to the vaccine. A systemic reaction is a side effect that occurs in the entire body, and can include fever, muscle pain, and/or chills. In total, 112 patients in the placebo group and 108 patients in the TAK-214 group had a systemic reaction. The most common ones were mild to moderate muscle pain, fever, and tiredness that lasted about 2-3 days.

No patients died during the study.

There were 5 cases of severe systemic reactions in the placebo group and 6 cases of severe systemic reactions in the TAK-214 group. Because those two numbers are so close to each other, the researchers could not decide that one is better or worse than the other.

Commentary

This article only summarizes the results of one study. Healthcare providers and researchers look at the results of many different studies to decide whether a medicine or treatment is appropriate for patients.

This is a phase II clinical trial. Drugs and vaccines must be tested in three phases of clinical trials in order to be approved by the FDA for marketing to the general public. Each phase typically takes years to complete, so we are still far away from possibly seeing TAK-214 approved by the FDA.

This study did not collect enough data to answer its main question, which was whether TAK-214 protects people from acute gastroenteritis caused by the GI.1 and GII.4 genetic variants of norovirus. This was because not enough patients got exposed to those variants during the study. In order to collect enough data, researchers would need more patients to be exposed. This is hard to do for two reasons:

  • Norovirus outbreaks are very hard to predict in the real world. We want the study to reflect what happens in the real world.
  • Researchers cannot expose patients to the norovirus on purpose, because it is unethical.

Therefore, in the future, if researchers design a phase III trial to test TAK-214, they need to enroll many more patients over a longer period of time in order to properly answer that question.

This study did not include patients from important population groups, such as children, pregnant women, or unhealthy patients with weak immune systems. Future studies would need to collect data on those populations.

The discovery that TAK-214 protects patients against the GII.2 variant is important. Since GII.2 is not one of the variants covered by the vaccine, this discovery gives hope that people can be protected against other variants, even if the vaccine does not cover them.

The amount of HBGA-blocking antibodies and pan-Ig in the blood samples gave researchers clues on whether the dose of TAK-214 was appropriate. Because the amount of HBGA-blocking antibodies and pan-Ig increased very rapidly in patients who received TAK-214, this meant that the patients had probably already been exposed to the norovirus before. (In other words, if the patients had never been exposed to norovirus before, the amount of HBGA-blocking antibodies and pan-Ig in the blood would have increased very slowly.) Based on this clue, the researchers figured out a few things:

  • Most (if not all) people have been exposed to norovirus earlier in their life, probably in childhood.
  • For people who have been exposed, one dose of TAK-214 is enough to get the body to “remember” that earlier exposure.
  • Therefore, one dose of TAK-214 is probably enough to protect most people.

Testing positive for HBGA-blocking antibodies and pan-Ig alone cannot prove that a person is protected from acute gastroenteritis, because sometimes a person can get infected even if he or she tests positive. Researchers use data about the HBGA-blocking antibodies and pan-Ig only to get a bigger picture of whether a person is likely to be immune to the norovirus.

The side effects caused by the vaccine were common side effects that are caused by most vaccines. For example, the flu vaccine also commonly causes pain, redness, swelling, and fever for a few days.

  • Link to the original study
    Efficacy of an intramuscular bivalent norovirus GI.1/GII.4 virus-like particle vaccine candidate in healthy US adults

This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2022 Lambert Peng

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