There are always statistical outliers, exceptions to the rule.
We can’t expect everyone to react to vaccines exactly the same way. Depending on one’s age, sex, and health status, the efficacy and safety profile of vaccines can differ by a wide margin. Thus, even though approved or authorized vaccines are safe and effective for the vast majority, there are and will always be statistical outliers.
Speaking of outliers, there’s no better time than a pandemic to identify them. As mass vaccination against the coronavirus disease 2019 (Covid-19) is going on, many reports of vaccine adverse reactions have surfaced. But note that such reports represent the tiny minority. The Covid-19 vaccines have undoubtedly saved many lives — imagine what the current death toll of Covid-19 of >3.8 million would be like if it drops by 90–95%. Still, one unnecessary death — even from a vaccine — is always one too many.
1. Frail elderly
The mRNA vaccine from Pfizer is the earliest to get emergency use authorization (EUA) from the Food and Drug Administration (FDA). Norway then started giving the Pfizer mRNA vaccine to the elderly in nursing homes — deemed a priority group at high risk of severe and fatal Covid-19 — as early as December 2020. (Age range: 65–74 years for youngest-old, 75–84 years for middle-old, and ≥85 years for oldest-old.)
This is even though the elderly were underrepresented in the Covid-19 vaccine clinical trials. For example, in the Pfizer mRNA vaccine phase 2/3 clinical trial, the participants’ median age was 52 years, with only 4.4% and 0.003% being over 75 and 85 years old, respectively. Although 46% of participants had at least one underlying medical condition (typically heart, lung, or liver diseases, obesity, or diabetes), only 0.1 % had dementia, 0.5 % had heart failure, and 1.0 % had cerebrovascular diseases — common diseases among the elderly. The frailty of participants was not measured.
From December 2020 to February 2021, Norway has administered the first dose of the Pfizer mRNA vaccine to nearly 30,000 frail elderly in nursing homes. The first suspected vaccine-related death in frail elderly was reported to the Norwegian Medicines Agency on 4 January 2021, and such reports have reached 142 as of May 2021.
This prompted the Norwegian Medicines Agency and Institue of Public Health to examine the first 100 reports of such vaccine-related deaths in frail elderly in nursing homes. Researchers first used the health and medical information from the frail elderly to estimate their remaining life expectancy. They then determined if the Pfizer mRNA vaccine shot had shortened the predicted life expectancy.
In a paper published in the Journal of the Norwegian Medical Association in May 2021, the researchers reported their findings: “In ten of the cases, a causal link between vaccine and death was considered probable, in 26 cases as possible and in 59 cases as unlikely. None were considered to be certain. The expert group considered five of the cases to be unclassifiable.”
- ‘Probable’ means it was more likely than not that the vaccine hastened death. This is not to say that the vaccine caused new adverse events, but rather that the frail elderly were so ill that they can’t even tolerate the usual mild side effects of vaccines like fever.
- ‘Possible’ means that the causal link between vaccine and death was just as likely as unlikely.
- ‘Unlikely means it was more likely than not that the vaccine is innocent.
- ‘Unclasifiable’ means insufficient information to judge anything.
None of the cases were definitive because the patients were old and frail and had multiple underlying medical conditions. This “means that a variety of factors could have contributed to the deaths,” the researchers explained. “It is therefore practically impossible to determine with any certainty how much of a role the vaccine played in the deaths.”
This finding, nonetheless, compels extra caution when vaccinating the frail elderly. The Norwegian Institute of Public Health recognizes this concern, stating that “For those who have a very short remaining life, the benefit of the vaccine may be marginal or irrelevant. Therefore, for very frail patients…and terminally ill patients, a careful balancing of benefit versus disadvantage of vaccination is recommended.”
2. Young-to-middle-aged females
Vaccine-induced thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS) was coined just a few months ago — to describe severe thrombosis (blood clots) plus thrombocytopenia (low platelets) that the DNA vaccines from AstraZeneca/Oxford (AZ/Ox) and Johnson & Johnson (J&J) can cause in rare cases.
The DNA vaccines from AZ/Ox and J&J use adenovirus as a carrier. This adenovirus technology or the DNA itself is thought to interact with platelets — a blood component that clots blood — to induce the formation of platelet factor 4 (PF4) antibodies that cause excessive blood clots. As platelets are being used up for the blood clots, platelet levels can drop too.
The AZ/Ox vaccine has also met the Bradford-Hill criteria of causation for VITT, responsible for at least 250 cases of VITT in Europe as of April 2021. As a result, some countries have stopped using the AZ/Ox vaccine, and some have restricted its use to the older age groups only.
Depending on the country, the rate of VITT ranges from one case per 26,000 to 127,000 doses of AZ/Ox vaccine and one case per 500,000 doses of J&J vaccine. It has a high fatality at about 25–50% (see red table). But VITT is treatable with immunoglobulins and non-heparin blood thinners, more so when early signs are recognized: shortness of breath, chest pain, leg swelling, persistent belly pain, severe headaches, blurred vision, and tiny blood spots under the skin beyond the injection site.
* Image from the author (reproduced from my previous article, with an update).
Although females younger than 50 years are overrepresented in VITT (see red table), the precise risk factors for VITT are still unknown. So, it’s tough to pinpoint what factors or variables that make the AZ/Ox or J&J vaccines unsafe for the tiny minority of young-to-middle-aged females. That said, authorities have warned that females aged 18–49 should be aware of the possible risk of VITT after getting the AZ/Ox or J&J vaccines.
The risk-benefit analyses of the AZ/Ox or J&J vaccines also depend on the situation (see figure below). In general, if Covid-19 cases are high, it’s better to get vaccinated soon. If Covid-19 cases remain low, however, females aged 18–49 may be better off waiting for or taking another vaccine. (There have been no reports of VITT from the mRNA or other vaccine types thus far.) Females with a history of disorders related to blood clots plus low platelets should also do the same. A history of blood clot disorder alone (without low platelets) doesn't appear to be a risk factor for VITT.
“Currently, we do not have any evidence that VITT is more common in people who have had blood clots before, people with a family history of blood clots, people on birth control or other hormones, people with autoimmune disease, people with low platelets or other platelet disorders, or pregnant people,” explained the Ontario COVID-19 Science Advisory Table. “It may be possible, however, that people with a history of heparin-induced thrombocytopenia (HIT) or cerebral sinus vein thrombosis (CSVT) with low platelets are at increased risk of VITT; they should receive an mRNA vaccine (Pfizer or Moderna) rather than an adenoviral vector vaccine.”
“It appears as though women under 40 are much more likely to develop blood clots than any other demographic [from the AZ/Ox or J&J vaccine],” agreed Ryan P. Gilley, Ph.D., a respiratory infectious disease scientist. “Following this line of thought suggests that women under 40 should receive higher priority than men of the same age, for the mRNA vaccines. Women from the ages of about 50–70, and most adult men should be the focus of the AZ and J&J shots, if available.”
3. General contraindications
Vaccine allergies exist. Anaphylaxis — severe allergic reaction —is a known risk from the mRNA vaccines. This is why people usually stay on site for 15–30 minutes after vaccination, in case of anaphylaxis happens, which is treatable with prompt norepinephrine shot available on standby. Thus, authorities have stated that persons with (1) known allergies to any of the vaccine ingredients, notably polyethylene glycol (PEG), or (2) severe allergy to the previous vaccine dose should avoid the said vaccine.
The Norwegian Institute of Public Health has also added a third contraindication to the Covid-19 vaccines: “Acute infectious disease with fever above 38 ° C.” This means that ill people with fever from an infection should not get vaccinated at the moment. After all, vaccines can induce fever too, and high fevers are dangerous by default.
The CDC has mentioned that people with Covid-19 should wait until Covid-19 is gone before getting vaccinated. Vaccines also come with short-term symptoms— such as fever, chills, fatigue, and general pain — which could worsen the ongoing Covid-19. Plus, vaccines are meant to prevent a particular infectious disease, so there’s not much point in vaccinating a person who is undergoing the said disease.
4. Unstable immune system: Late-stage cancer
As the immune system is thought to be the most complicated entity besides the brain, disorders in the immune system are very difficult to decipher. We don’t know what an unstable immune system looks like precisely, and how a vaccine might interact with an unstable immune system. Plus, persons with unstable immune systems — such as autoimmune diseases or cancers — were excluded from the Covid-19 clinical trials.
A case study published in May 2021 in Nature, a world-ranking journal, describes a 58-year-old male with stage IV colon cancer who got the Pfizer mRNA vaccine. Five days later, he manifested cytokine release syndrome (CRS), a severe systemic inflammatory response. Fortunately, anti-inflammatory drugs saved his life. He was tested negative for SARS-CoV-2, ruling out Covid-19 as the cause of the CRS. He was also treated with anti-PD-1 immunotherapy, which activates and directs immune cells to kill cancer cells. But the authors suspected that activating the immune system this way may have lead to uncontrolled immune system overreaction from vaccination.
“The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor,” the authors concluded. But the authors advised that patients with cancer remain prioritized for vaccination, as they are also at high risk for severe and fatal Covid-19.
Although a case study is published mainly to describe a very rare problem, it also means that such a rare problem might be underreported. After all, investigating and publishing a case study takes time and resources that are often limited. I recently had the privilege of working freelance for a physician professor, where he shared with me his experience with seven patients with stage IV cancers that were well-controlled for over five years, only to experience a sudden cancer progression right after the Covid-19 vaccine. He theorized that “vaccination disturbed delicate balance in immune surveillance of patients’ metastatic disease by recruiting immune cells of the adaptive immune system towards the vaccination site.”
In essence, the physician professor suggests that immune cells needed to control late-stage cancer might get re-directed away to mount a vaccine immunization response. His concerns are not alone. A research review published earlier this year also mentioned that “it is important to assure the vaccination would not cause a further T-cell exhaustion state which may have already been induced by [cancerous] tumour cells.”
(T-cells are part of the adaptive immune system responsible for killing abnormal cells — such as cancer or virus-infected cells — and creating immune memory of a particular infection. Most vaccines do activate and train T-cells to respond more efficiently to a given infection. But T-cells supply is limited and can be exhausted.)
Moreover, many studies have found that Covid-19 vaccines are less or not effective in patients with cancers, especially blood-related cancers and patients on chemotherapy that are both known to harm immune cells in the blood. Only one of these studies examined the Pfizer mRNA vaccine’s safety and, thankfully, found no signals of vaccine toxicity among 151 patients with cancers of various types. This is except for one cancer patient on immunotherapy who developed an abnormal liver disorder that required hospitalization, but it’s inconclusive if the mRNA vaccine caused this. That said, this is only one study, so more safety data is always welcomed, particularly for frail patients with late-stage cancers.
5. Unstable immune system: Autoimmunity
Autoimmune disorders are another tricky immunological topic that comes in various forms. People with or at risk for autoimmunity are also at risk for post-vaccine autoimmunity, also called Shoenfeld’s syndrome.
Shoenfeld’s syndrome can include both symptoms (chronic fatigue, muscle weakness, sleep problems, cognitive impairments, fever, and dry mouth) and diseases (arthritis, lupus, type I diabetes, dermatomyositis, Guillain-Barré syndrome, demyelinating disorders, thrombocytopenia, and vasculitis). Speaking of thrombocytopenia and vasculitis (inflamed blood vessels), VITT can be viewed as a type of Shoenfeld’s syndrome too.
For mRNA vaccines, autoimmune risks have been noted earlier by the inventor of mRNA vaccine himself, Drew Weissman, MD, Ph.D., professor of medicine. “A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity,” the professor stated in a 2018 research review. “Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken.”
A few published studies have looked at how persons with autoimmunity fare with the Covid-19 vaccine. One case series noted that six out of 491 persons with autoimmune inflammatory rheumatic diseases (AIIRD) had pre-existing herpes zoster infection, compared to zero in healthy controls. After getting the Pfizer mRNA vaccine, however, all six developed herpes zoster reactivation. Five of them had mild herpes zoster skin disease, two had arthritis flares, and one had severe herpes zoster shingles. “COVID-19 [Pfizer] mRNA vaccine might provoke reactivation of herpes zoster in patients with AIIRD,” the authors concluded. “Epidemiologic studies on the safety of COVID-19 vaccines in patients with AIIRD are warranted.”
Moving on, three cohort studies found no significant difference in rates of Covid-19 vaccine (i.e., Pfizer, Moderna, and AZ/Ox) adverse events among patients with autoimmune diseases versus non-autoimmune control groups. The first study involved 505 patients with AIIRD or multiple sclerosis; the second involved 513 AAIR patients; and the third involved 686 AIIRD patients. In the first study, however, 5% (26 out of 505) reported that their autoimmune condition worsened after vaccination. The third study also noted that after vaccination, five AAIRD patients manifested herpes zoster reactivation; one developed severe herpes zoster shingles; and two died, one from vasculitis plus sepsis and the other from a heart attack.
But it’s uncertain if the vaccine is the cause of these adverse events, as these studies did not include unvaccinated persons with autoimmunity as a control group for comparison. Maybe that 5% is the background rate for autoimmune disease progression for that specific study cohort. Maybe that two deaths are also what’s expected, regardless of the vaccine. Still, at least the studies presented in this section assure us that the Covid-19 vaccines are safe for the vast majority of autoimmune patients.
At any rate, it must be noted that these situations are the outliers, which must be weighed against the common hazards of Covid-19. Although the fatality rate of Covid-19 differs by age group, about 3.9 million out of 181 million cases (~2%) globally have ended in death as of today. Besides death, Covid-19 also poses other health burdens, such as the long-COVID syndrome, post-intensive care unit (ICU) syndrome, and increased risk of other diseases in the future. Thus, in regions where Covid-19 is prevalent, prompt vaccination is often the safer choice.
(Note: The FDA and CDC have lately confirmed myocarditis — inflamed heart muscles — as a rare side effect of mRNA vaccine in young men, which is non-severe and often heals on its own. So, such cases of mRNA vaccine-induced myocarditis are not considered dangerous in this article.)
But if there’s no risk of getting Covid-19 in the coming months — such as those who have got Covid-19 recently or reside in regions with low Covid-19 cases —a tiny minority of people may want to adopt the wait-and-see approach. Maybe as more research gets done, we will know which types of vaccines are best suited for the frail elderly, young-to-middle-aged females, persons with vaccine allergies, and patients with unstable immune systems.
Last but not least, private consultations with medical professionals should take precedence over this article. After all, your situation may be more unique than what’s covered (somewhat superficially) in this article.
This article was previously published in Microbial Instincts with minor changes.
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