By Julie Beal
Moderna has been testing mRNA vaccines on humans for six years now. There were lots of ‘adverse events’ during the clinical trials and most of them were classed as desirable or ‘solicited’. A number of reactions were described as being serious or severe, though, and one death was reported, but none of these events were considered to be related to the mRNA products being tested. So what actually happened to the people who experienced adverse events during these trials? Did they get better? Does anybody know?
What’s Going On (Video)
Well…. maybe we should ask PPD. They’re a company that conducts clinical trials and they were used by Moderna, according to a 2017 presentation for the 35th Annual JP Morgan Healthcare Conference. So are PPD investigators well-trained in genetics? Their website states, “Most clinical trial investigators are physicians in private practice. … No previous experience as an investigator is needed to qualify.” This is one of the biggest problems with genetic potions – doctors aren’t taught about genetics, or lipid nanoparticles or mRNA! They don’t know what to make of the adverse reactions to the ronavax because they don’t understand the mechanism by which they operate, so it’s possible the doctors in the trials wouldn’t have known how to assess reactions either.
[There really needs to be a new name for these things because they’re not vaccines. They merely have the potential to work in a similar way to old-fashioned vaccines, but this will depend on the host doing the work, and cannot guarantee the actual ‘dose’ being delivered. Really, they’re like kits for making vaccines so the final product can vary.]
H10N8 Influenza vaccine (mRNA-1440)
- This was the first trial, begun in 2015 in Germany with company Parexel (involved in the TeGenero Incident)
- Discussed in an article published in 2017, ‘Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses’
- The Phase 1 “first-in-human” trial involved 201 participants and the study product was called VAL-506440 (part of the Valera team) and ran from December 2015 to October 2018
- 145 people were given mRNA, 35 got a placebo
- The name was then changed from VAL-506440 to mRNA-1440
- Details of both influenza vax trials were given in Form S-1, filed with the Securities and Exchange Commission on the 9th of November, 2018: “Overall, up to the 100 µg IM [intramuscular] dose[i], mRNA-1440 was well tolerated. …. In the 400 µg IM dose group, two out of the three participants developed severe solicited adverse reactions (erythema, headache) within 24 hours of the first vaccination. These events met pre-specified study pause rules, and after safety committee review, further vaccinations at this dose level were stopped. These events resolved spontaneously without the need for medical intervention or medications.
- Three severe unsolicited AEs (separately back pain, tonsillitis, and ruptured ovarian cyst) and 2 serious AEs, or SAEs, (separately cholecystitis and ruptured ovarian cyst) were reported and deemed unrelated to mRNA-1440. 124 unsolicited AEs were reported in the IM groups.
- The most common unsolicited AEs were upper respiratory tract infection, back pain, pharyngitis, and oropharyngeal pain. No adverse events of special interest, or AESIs, or cases of new onset of chronic illness were reported.”
- In the 75 µg dose group, two people experienced “severe solicited AEs of fatigue and injection site swelling following first vaccination”, so they didn’t get a second dose.
- A table shows the number of solicited adverse events for the H10N8 vaccine reported in the trial but omits data for the people who received the 75 µg and 400 µg doses. The first dose lists data for 83 people who were dosed with mRNA-1440 and 35 who got the placebo. These figures change for the second dose, where only 80 people got the vax and 27 got the placebo.
- Most people had injection site pain, about half had myalgia, and there were a number of reports of headache and fatigue. One person in the placebo group had a severe headache, but there were “no SAEs in the dosed group that remained.”
H7N9 Influenza vaccine (mRNA-1851)
- The results of the Phase 1 trial for H7N9 vaccine were reported in Vaccine in 2019. The vaccine was originally called VAL-339851 but this was changed to mRNA-1851.
- They tested three different dose levels (10, 25, and 50 µg) using slightly different vaccination schedules.
- 156 subjects were enrolled ; 36 received a placebo. Ten subjects withdrew from the study, but the reasons for this are not given. There appear to be several people missing from the trial data, because each table consistently reports the placebo group containing 36 people, which means there should be at least 110 people receiving the vaccine. However, the tables and diagrams show a varying number of people in each group (and the dosing schedule is difficult to decipher).
- “Overall, up to the 50 µg IM dose of mRNA-1851 was well tolerated. The majority of possibly- and probably-related unsolicited AEs were > grade 2 laboratory abnormalities and occurred at similar rates in vaccine and placebo groups.
- Four severe unsolicited AEs were deemed possibly related to vaccination: two cases of increased alanine aminotransferase (one 50 µg, one placebo), one case of increased aspartate aminotransferase (50 µg), and one case of thrombocytopenia (placebo). All cases were asymptomatic and resolved without intervention.
- Five SAEs (separately unintentional firearm-related death, testicular cancer, pancreatitis, facial cellulitis, and exacerbated hypertension) were reported and deemed unrelated to mRNA-1851.
- 124 unsolicited AEs were reported in the IM groups. The most common unsolicited AEs were upper respiratory tract infection, back pain, pharyngitis, and oropharyngeal pain. No AESIs or cases of new onset of chronic illness were reported.”
Respiratory syncytial virus (RSV) vaccine (mRNA-1172/mRNA-1777)
- See ‘Prophylactic vaccines – Phase 1 datasets’ (2019)
- “mRNA-1777 was well-tolerated at first three dose levels in younger and older adults—The highest dose arm (dose four) in the older adult cohort was not as well tolerated but did not result in significant safety concerns—No treatment-related SAEs or TEAEs” [treatment emergent adverse events]
- Moderna decided to abandon plans to move the vaccine to Phase 2 trials
- Plans were announced to develop mRNA-1345 as a pediatric RSV vaccine for young children (aged 12-59 months)
- “The Phase 1 trial for mRNA-1777 in Australia generated safety and tolerability data and demonstrated immunogenicity and has been completed; further development of mRNA-1777 has been paused pending data from the ongoing Phase 1 trial for mRNA-1172 sponsored by Merck”
- 200 subjects were involved, but “As of September 2018, the highest dose level, which was evaluated in older subjects only, dose level four, was not as well tolerated as the lower dose levels.”
- “…. we have observed 15 SAEs in nine subjects, all of which were deemed unrelated to study product. These SAEs occurred approximately one to ten months from receipt of study product and included aortic aneurysm repair, paralytic ileus, spinal decompression, death from pre-existing cardiomyopathy, hernia, transient ischemic attack, peripheral vascular disorder, vasovagal syncope, diagnosis of non-small cell lung cancer, anterior cruciate ligament tear, left knee tendon tear, right knee tendon tear, left patella dislocation, right patella dislocation, and bilateral patella tendon repair. Based on the interim safety, tolerability, and immunogenicity data in collaboration with Merck, we have opted to pause further development of mRNA-1777. Merck is conducting a Phase 1 trial with mRNA-1172 in the United States.”
Chikungunya Virus Antibody (VAL-181388)
- Developed with DARPA (Defense Advanced Research Projects Agency)
- The Phase 1 trial involved 60 participants and lasted from 15th of August 2017 to 1st of November 2019
- DARPA released a statement saying, “The researchers have demonstrated that it is feasible to use mRNA sequences to produce and scale a highly potent antibody response against an infectious disease target”.
Cytomegalovirus (CMV) vaccine (mRNA-1647) [ii]
- The CMV vax contains six mRNAs in a proprietary LNP.
- Tests were done on mice and non-human primates, and the results were published in Vaccine in 2018.
- There were said to be no vaccine-related serious adverse events in the Phase 1 trial. “The most common solicited local adverse reaction, or AR, was injection site pain. The most common solicited systemic ARs were headache, fatigue, myalgia and chills.” A Phase 2 trial was planned for the United States.
- The Phase 1 clinical trial of mRNA-1647 enrolled 181 healthy adult volunteers.
- Grade 3 solicited AEs were said to include: “fatigue (0-27% of a given dose cohort), chills (0-27% of a given dose cohort) and fever (0-33% of a given dose cohort).” – The statistics don’t offer much information reported like this!
- There was also a Grade 4 AE related to an elevated partial thromboplastin time (meaning it takes longer to form blood clots). This was said to be resolved by the next lab test.
- Phase 2 Start and Phase 3 Planning: “mRNA-1647 is the first mRNA vaccine for an infectious disease to enter a Phase 2 study” involving approximately 252 people. “This Phase 2 study is testing the intended Phase 3 formulation, which contains the same lipid nanoparticle (“LNP”) used in the Phase 1 study.”
- “We have solicited and received Type C meeting feedback from the U.S. Food and Drug Administration (“FDA”) on the preliminary design of the pivotal trial. We believe this can be achieved with a trial with no more than 8,000 participants and feasibility assessments of study sites has already begun across North America and Europe. The pivotal trial design will be finalized after discussion with the FDA and other global health authorities.”
- “Manufacturing and planning are already underway for the pivotal Phase 3 study, which we expect to start in 2021.” (This was announced in early February, 2020!)
hMPV/PIV3 vaccine (mRNA-1653)
- First, they tested it on mice, rats, and monkeys.
- The Phase 1 trial was conducted in Texas and Nebraska between 2017 and 2019.
- The mRNA-1653 Phase 1 study tested four dose levels of mRNA-1653 (25, 75, 150, and 300 µg). “No SAEs, adverse events of special interest, or adverse events leading to withdrawal were reported. Injection site pain was the most commonly reported AE and the most common grade 3 AE.”
- Participants in the Phase 1 trial reported unsolicited related AEs which included mild to moderate chills, hot flushes, diarrhea, pyrexia, temperature intolerance, elevated WBC count, headache and erythematous rash, as well as severe injection site pain, prolonged PT and myalgia. All of the severe events are said to have occurred at the 300 mcg x 2 dose level.
- 95 people were dosed with the vax and 30 people received a placebo. Reactions were said to include: i) 33 ‘events’ in the vaxed and 5 ‘events’ in the placebo, ii) 11 ‘related events’, iii) 3 ‘Grade 3+ events;, iv) 3 ‘related grade 3+ events’, v) 10 ‘medically attended events’. Somehow, though, there were “no serious adverse events (SAEs), adverse events of special interest, or adverse events leading to withdrawal”.
- With these “positive interim results”, Moderna then planned a Phase 1b trial for mRNA-1653 in the United States in healthy adults and children aged 12-36 months.
- On the 3rd of March, 2020, it was reported that Stéphane Bancel, Moderna’s Chief Executive Officer, claimed, “The Moderna team is working diligently to start the Phase 3 study in 2021.”
Zika Virus (mRNA-1325 and mRNA-1893)
- Developed with BARDA (Biomedical Advanced Research and Development Authority)
- The Phase 1 trial was 2017-2019, with 90 participants.
- “Both the 100 and 250 μg dose levels were generally well tolerated. There was a trend towards more observations of local erythema and swelling/induration at the injection site with higher dose levels, in particular after the 2nd vaccine administration. There was a trend of more solicited systemic adverse events with the 250 μg, after the second administration.”
- They also tried a lower dose – “Following a 2-dose vaccination schedule of mRNA-1893 given 28 days apart, the 10 µg and 30 µg dose levels were both generally well-tolerated, and there were no vaccine-related serious adverse events (SAEs) or adverse events of special interest (AESI). The most frequent solicited adverse reaction was local pain at the injection site.” (But note the grade 3 adverse reactions in red text listed on slide 7 in this presentation.)
The European Medicines Agency (EMA) Report on mRNA-1273
The clinical trials described above also refer to various changes in the blood after receiving an mRNA vax, and similar changes are mentioned in the EMA report as well.[iii] For example, “Haematology changes included increase in white blood cells, neutrophils, and eosinophils and decreased lymphocytes; coagulation changes included increase in fibrinogen and activated partial thromboplastin time; and clinical chemistry changes included decrease in albumin, increase in globulin, and a corresponding decrease in albumin/globulin ratio.” These changes are then dismissed with one short sentence: “Clinical pathology changes generally reversed or were reversing by the end of the 2-week recovery period.”
It might as well say, “Ach, don’t worry, it’s not a problem, it only lasted a couple of weeks or so!”[iv]
[i]Doses – the adult dose of mRNA-1273 contains 100 micrograms (100 μg) of mRNA, which is a fairly high dose (previous trials tested 25, 50, 75 and 100 μg doses on humans; animals were also tested with a range of doses, but they were each given a dose that was based on their body weight, e.g. 1 μg per kilogram for primates.) Moderna’s Betacoronavirus vaccine patent notes the dose level required would depend on the disorder being targeted, how severe it is, the type of mRNA being used, and individual characteristics such as age, weight, general health, sex and diet, and possibly other factors such as taking other drugs.
[ii] Adverse events for the CMV, HMPV/PIV3, and Zika vaccines are also described in
‘Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults’ – the statistics seem to be a good example of how they can be used to ‘frame’ a good result.
[iii] Some examples of how the EMA assessed the safety of mRNA-1273:
- “The product-specific Study 2308-123 was not conducted in GLP-compliance, and exhibits major procedural/methodological limitations…. However, as no clear differences in toxicity are observed between study 2308-123 and the repeated dose toxicity studies conducted with other LNP-mRNA products, the latter studies are considered sufficient to support clinical development….”
- “…. the observed increases in plasma potassium levels in the submitted rat GLP repeated dose toxicity studies are consistent with biologic variability in rats, and were reversed or were reversing after recovery, and were not considered test-item related by the study director and/or clinical pathologist.”
- “The observed spleen changes were minimal and caused by a transient systemic inflammatory response to LNP administration and/or to the expected compensatory response. …. it is considered that the observed spleen findings could only bear limited relevance for humans.”
- “…. it is considered that these severe local inflammations bear no clinical relevance”
- “… such a risk is considered low in humans”
- “No dedicated studies on absorption, metabolism, and excretion for mRNA-1273 have been submitted. This is generally acceptable with regards to the nature of the vaccine product.”
- “…. the extent of the submitted repeated dose toxicity programme is deemed acceptable. …. the GLP and procedural/methodological limitations of study 2308-123 are accepted.”
- “….. lipid components contained in the final formulation, i.e. PEG2000-DMG, DSPC and cholesterol, were not separately tested but are contained in the formulation tested in the in vivo genotoxicity studies, which is acceptable.”
- “No carcinogenicity studies were submitted. This is scientifically acceptable and in line with relevant guidelines on non-clinical development of vaccine candidates.”
[iv] Moderna/the EMA seem to be claiming that there are 3 different types of possible reaction to their vaccines; 1) reacting to the mRNA itself, usually referred to in the EMA report as being the ‘test-article’, 2) reacting to the LNP formulation, and 3) the overall ‘immune response’ to the stuff the mRNA causes the body to produce.
For example, it’s said that toxicology results for different products (i.e. containing different types of mRNA) were “quite similar” so they reason that the observed toxicities could be due in part to “the novel LNP formulation”, but they also claim the toxicities could be “caused by the immunologic responses” that happen when the mRNA starts to be turned into a vaccine by the body. During a meeting (Moderna Third Quarter 2019 Conference Call) with executives from Merrill Lynch, JPMorgan Chase, Morgan Stanley, Goldman Sachs, and ROTH Capital Partners, Tal Zaks was asked how long it would be until there were safety results from trials with the antibody against chikungunya. Zaks replied: “Several weeks, I would say. I don’t think it’s going to be much longer than that. The reality is you’ve seen the adverse event profile to-date. It really is a function of the LNP, as I understand it, more than the protein that we make. …. I’ve not seen anything that leads me to expect that there’s a long-term challenge here. I think the safety profile, within a week, we’ll describe what it is.”
Moderna are planning to make more and more vaccines and they now consider their formulations to be “derisked”. In a presentation at the Second Annual Vaccines Day (April 2021), they described plans to extend trials of their hMPV/PIV3 vaccine (mRNA-1653) to toddlers; there will be 24 Adults in one cohort and 51 seropositive children (aged 12-59 months) in four additional cohorts. They’re also working on a prefusion version of RSV.
Moderna’s “strategy for combating COVID-19” is to develop two new variants of their current coronavirus vaccine. One codes for the South African variant and is called mRNA-1273.351. The other vaccine contains a mix of the Wuhan and South African variants and is called mRNA-1273.211.
“We will continue to bring variant booster shots until COVID-19 is under control.”
“We are building a go-to-market approach for variants and combos”
“Based on a 2-dose efficacy of 90%, COVID-19 vaccine use during a pandemic between $460-$540 per 2-dose series was found cost-effective at $50K/ QALY [quality of life years] for the overall population (adults 18+) We are incorporating cost-effectiveness into our value based approach for the endemic market”
Moderna are also working on something new – gene editing with mRNA. They’ve partnered with Vertex to do gene editing in lungs.
See Julie Beal’s entire Rona archive HERE.
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