Multiple Increasing Vaccine Adverse Events Safety Signals for Older Adults

1. Introduction

Aging-associated declines in immune system responses, a process named immunosenescence, result in weaker immune responses to new pathogens and vaccines. For improved protection against influenza, multiple high-dose vaccines are provided to the elderly. Immune responses to vaccines are reflected in associated adverse events. The Vaccine Adverse Event Reporting System (VAERS) collects population samples of adverse events (AEs) for the detection of associated safety signals. Safety signals specific to vaccine constituents can be detectable above expected background occurrence frequencies by comparing AE frequencies between different vaccines.

Characteristics of immunosenescence for antibody and T-cell responses have been observed in multiple studies for COVID-19 vaccines. Lower neutralization of SARS-CoV-2 infection was observed for IgA and IgG serum from elderly recipients, accompanied by lower T cell responses after the first dose of the Pfizer-BioNTech BNT162b2 vaccine [1]. Similar results were observed for 71 and 149 elderly COVID-19 Pfizer-BioNTech BNT162b2 vaccine recipients in two studies [2,3]. A study including 105 older long-term care facility residents found dramatically impaired humoral and cellular memory responses three months after the first COVID-19 Pfizer-BioNTech BNT162b2 mRNA vaccine dose [4]. A study of 138 nursing home residents found lower neutralization for residents receiving the COVID-19 Pfizer-BioNTech BNT163b2 vaccine (4-fold lower) and the COVID-19 Moderna mRNA-1273 vaccine (2-fold lower) [5]. A study of 165,755 nursing home residents in Sweden found higher mortality for unvaccinated residents and residents with no prior COVID-19 infection who had not received a COVID-19 vaccine or booster dose within the last 90 days [6]. Lower mortality is observed for COVID-19 vaccinated compared to unvaccinated individuals [7].

To detect possible safety signals in the elderly, AEs were retrospectively examined in VAERS for 10-year age groups for all vaccines. As anticipated, multiple AEs were observed with frequencies that correlate with increasing age, likely associated with immunosenescence. Unexpectedly, the AE death appears to have additive risks for coadministered vaccines with higher frequencies; this may indicate unknown causative constituents like manufacturing contaminants within specific vaccines. It is strongly recommended that COVID-19 vaccines not be coadministered with other vaccines without prior clinical trials of these vaccine combinations that include elderly individuals.

2. Materials and Methods

Materials

State all the materials used in the study, and include the manufacturer’s name, city and country of origin.

The VAERS database [8] was retrospectively examined for AEs with the Ruby program vaers_tally_age10.rb [9]; this program summarizes AEs by 10-year age groups. The download of VAERS data includes all AEs reported from 1990 to October 31, 2025. This program calculates the frequencies of reported AEs normalized to 100,000 VAERS reports: AE normalized frequency = (age group observed AEs/all vaccine AEs)*100,000 for each single administered vaccine or coadministered vaccines. For reference, the names of coadministered vaccines are joined with the plus symbol. Vaccines and vaccine combinations including the text “no brand name”, “foreign”, “unknown”, and “vaccine not specified” were excluded to avoid possible reporting biases due to the possibility of underrepresentation of less severe AEs resulting in increased normalized frequency estimates. This retrospective study examines the age groups 50-59, 60-69, 70-79, 80-89, 90-100, and 100-109. VAERS AE names and spelling have not been changed. The day of onset data was examined with the Ruby program vaers_slice5.rb [9]. Microsoft Excel was used for median calculations, data sorting, and creating figures.

3. Results

For the age group 80 to 89 and vaccines with at least 1,000 VAERS AEs, the top AEs are illustrated for five COVID-19 vaccines (Table 1A) and Influenza seasonal (Fluzone high-dose), Pneumo (Pneumovax), Pneumo (Prevnar13), Zoster (Shingrix), and Zoster live (Zostavax) (Table 1B); AEs selected were in the top 50 by normalized frequency for at least two vaccines. Multiple AEs in the COVID-19 AEs list (Table 1A) do not overlap with the top AE list for the other five vaccines; these AEs are illustrated in Table 2. Other top AEs for the five non-COVID-19 vaccines did not overlap the COVID-19 top list: back pain, blister, cellulitis, herpes zoster, hypoaesthesia, injected limb mobility decreased, injection site induration, injection site inflammation, injection site pruritus, injection site rash, injection site reaction, injection site warmth, mobility decreased, muscular weakness, musculoskeletal pain, neck pain, oedema peripheral, paraesthesia, rash erythematous, rash pruritic, skin warm, swelling, tenderness, tremor, and urticaria. The AE death normalized frequencies are illustrated in Figure 1, and AE fall in Figure 2 for multiple vaccines. The AE death normalized frequencies by manufacturing lot number are illustrated for selected lots for three COVID-19 vaccines (Figure 3). The day of onset for AE death is illustrated in Table 3.

4. Discussion

4.1. Frequent Adverse Events in the Age Group 80 to 89

Aging likely negatively impacts AEs following immunizations. The top AEs for vaccines with more than 1,000 VAERS reports are shown in Table 1. For COVID-19 vaccine recipients, COVID-19 infection and associated AEs are only seen associated with the COVID-19 vaccines (Table 1); age group comparisons for these AEs are illustrated in Table 2. For the age group 80 to 89 vaccine recipients of the COVID-19 Janssen vaccine, 1 in 3.3 (30.5%) reported COVID-19 infection, and 1 in 7.4 (13.6%) died (Table 1A). The normalized frequency for AE death for the COVID-19 vaccines was 1829 for the COVID-19 (Janssen), 1409 for the COVID-19 (Moderna), 646 for the COVID-19 (Moderna bivalent), 1260 for the COVID-19 (Moderna Mnexspike), 629 for the COVID-19 (Novavax), 1063 for the COVID-19 (Pfizer-BioNTech), and 887 for the COVID-19 (Pfizer-BioNTech bivalent). For all ages, higher numbers of deaths were reported following the second dose compared to the first dose of the COVID-19 Pfizer-BioNTech vaccine (3487 first dose and 4654 second dose) and the COVID-19 Moderna vaccine (2931 first dose and 3749 second dose). For the age group 80 to 89 vaccine recipients of the COVID-19 Pfizer-BioNTech vaccine, 1 in 4.9 (20.5%) reported COVID-19 infection, and 1 in 12.4 (8.1%) died (Table 1A). For the COVID-19 AEs illustrated in Table 2, the majority fit the pattern of increasing normalized frequency by increased age, except for chest pain and oropharyngeal pain. Note the chest pain AE may have associations with myocarditis and pericarditis AEs with inverse age risks following COVID-19 immunization for both genders [10].

Multiple COVID-19 lots exhibit higher normalized frequencies than the overall average for all ages for the AE death (Figure 3 and Supplemental Table S1). For the COVID-19 Janssen lots 1805031 (4731), 1802070 (4676), and 212C21A (4651), plus 14 additional lots, were higher than the overall 1829 (Supplemental Table S1). A total of 175 COVID-19 Moderna lots with at least 4 death AEs exceed the overall 1260, including lots 207H23-2A (68,292), 3043159 (57,500), and 3046731 (44,186), with the normalized frequency for 12 lots higher than 10,000 (> 1 in 10) (Supplemental Table S1). Five COVID-19 Moderna bivalent lots had at least four AEs, including AS7184B (6756), AS7180B (4938), and 020H22A (3478), which were higher than the overall 646 (Supplemental Table S1). A total of 174 COVID-19 Pfizer-BioNTech lots exceed the overall AE death normalized frequency of 1063, including EK4238 (19,512), EK4242 (15,789), and E10140 (12,195) (Supplemental Table S1). While normal distributions are expected, the very high normalized frequencies for the COVID-19 Moderna, COVID-19 Moderna bivalent, COVID-19 Pfizer-BioNTech, and possibly COVID-19 Janssen vaccines are consistent with manufacturing contaminants as likely causative components [11].

Endotoxins are one possible manufacturing contaminant. Lipopolysaccharides (LPS), also known as endotoxins or pyrogens, are constituents of the outer membrane of gram-negative bacteria. Endotoxins are a common manufacturing contaminant of vaccines. Endotoxin levels can vary widely by vaccine [12,13]. To minimize endotoxin contaminants, nanoparticles should be manufactured under endotoxin-free conditions [14].

4.2. COVID-19 Breakthrough Infection

Individuals are getting the COVID-19 immunization to avoid COVID-19. It seems counterintuitive that the top AE associated with COVID-19 immunization (Table 1A) is COVID-19. The coronavirus family is well-known for infecting phagocytic immune cells using Fc receptor binding to infect additional host cells [15]. The process of antibody-dependent enhancement of disease (ADE) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been proposed [16] and supported by clinical evidence [17]. The proposed ADE infection of immune cells has been demonstrated to be sensitive to the antibody titer level for the SARS-CoV-1 virus [18]. Hence, until COVID-19 vaccine recipients reach very high Spike protein antibody titer levels, the vaccine recipients have possibly higher infectivity potential than non-vaccinated individuals. Likewise, as the Spike antibody titers naturally decrease after several months, breakthrough infections of fully vaccinated and boosted individuals are being observed. The current recommendations for COVID-19 booster shots every six months should maintain ongoing very high levels of Spike protein antibodies.

4.3. Death Adverse Event

The risk of death increases with increased age. For comparison purposes, an upper limit for background AE death can be estimated roughly as 252 per 100,000 VAERS reports using the value for Zoster (Shingrix) (Table 1B); given this, the normalized frequency for COVID-19 Janssen is 81 times higher than this background rate (20,500 / 252), and COVID-19 Pfizer-BioNTech is 32 times higher than this background rate (8,089 / 252). The background deaths per 7 days per 100,000 individuals in the United States is 109 [19]. Normalized frequencies for AE death for age groups 50-59, 60-69, 70-79, and 80-89 for multiple vaccines and several coadministered vaccines are illustrated in Figure 1. The normalized frequencies for death appear additive for COVID-19 Janssen and COVID-19 Moderna (18.2%), COVID-19 Janssen and COVID-19 Pfizer-BioNTech (22.2%), and COVID-19 Pfizer-BioNTech bivalent + Influenza seasonal (Fluzone high-dose quadrivalent) (6.9%) (Figure 1). The normalized frequency for the COVID-19 Janssen vaccine is 1829 (1.8%), and the COVID-19 Pfizer-BioNTech vaccine is 1063 (1.1%). The normalized frequency for the COVID-19 Janssen vaccine age group 80 to 89 is 11.2 times higher than for all ages; the normalized frequency for ages 80 to 89 for the COVID-19 Pfizer-BioNTech vaccine is 7.6 times higher than for all ages. The majority of deaths AEs are reported with an onset of a few days (Table 3); it is well-known that as time increases, the likelihood of reporting AEs to VAERS decreases. The normalized frequencies for AE death for COVID-19 vaccine recipient age groups 70 to 79 and 80 to 89 represent multiple safety signals (Figure 1). The normalized frequencies for AE death for Pneumo (Pneumovax), Pneumo (Prevnar13), RSV (Abrysvo), and Zoster live (Zostavax) age group 80 to 89 may also represent safety signals (Figure 1). Top overlapping AEs with death that do not overlap the COVID-19 top AEs (Table 1A) include autopsy, cardiac arrest, cardio-respiratory arrest, endotracheal intubation, general physical health deterioration, hypotension, loss of consciousness, mechanical ventilation, mental status changes, myocardial infarction, oxygen saturation decreased, positive airway pressure therapy, pulse absent, respiratory arrest, respiratory distress, respiratory failure, resuscitation, septic shock, syncope, unresponsive to stimuli, and vaccination failure. Deaths have been linked with the COVID-19 Pfizer-BioNTech vaccine [20]. Excess deaths have been observed after repeated COVID-19 vaccination in Japan [21]. Florida residents who received the COVID-19 Pfizer-BioNTech BNT162b2 vaccine were observed with significantly higher risk for 12-month all-cause mortality compared to matched COVID-19 Moderna mRNA-1273 vaccine recipients [22].

Hypothesis 1:  

Immunization with a COVID-19 vaccine correlates with SARS-CoV-2 infection in elderly individuals.

Multiple days are anticipated for a SARS-CoV-2 infection post-immunization, followed in some individuals by COVID-19-associated death, with COVID-19-associated death occurring multiple days after infection. Defining any individual receiving a COVID-19 vaccine as vaccinated, these cases all represent COVID-19 vaccine breakthrough infections; many cases in VAERS are reported after the first of two paired mRNA vaccine doses, but more cases follow the second dose. ADE may be contributing to the severity of COVID-19 in elderly individuals [16].

Hypothesis 2:  

Novel safety signal detected is associated with multiple vaccines, including the COVID-19 Moderna, COVID-19 Pfizer-BioNTech, COVID-19 Moderna bivalent, and COVID-19 Janssen for AE death; elevated normalized frequencies associated with manufacturing lots are supportive of unknown manufacturing contamination as a likely causative component.

VAERS data indicate elevated additive risks for coadministration of two or more vaccines with elevated AE death normalized frequencies. VAERS data are consistent with a rapid onset in days for this safety signal. Deaths associated with the Hypothesis 2 model are likely independent of SARS-CoV-2 infection, but overlaps between these two independent etiology models can occur randomly. Note that both the COVID-19 Pfizer-BioNTech BNT162b2 and the COVID-19 Moderna Spikevax mRNA-1273 vaccines were found to have residual plasmid DNA and SV40 promoter-enhancer sequences in some vaccine batches [23]; while this is of major concern with regards to long-term expression of the Spike protein within vaccine recipient bacteria cells, any relationship to immediate-onset adverse event death is unknown. This does illustrate contamination of vaccine batches with unintended constituents.

4.4. Fall Adverse Event

The risk of falling following immunization has been previously identified [24]. The AE fall is in the top 50 ranked AEs for multiple vaccines (Table 1). This study demonstrates an undetected age risk factor for the fall AE (Figure 2). The normalized frequencies for the AE fall are much higher for COVID-19 vaccines and coadministered combinations including a COVID-19 vaccine than for non-COVID-19 vaccines (Figure 2). There may be some signature overlaps with the AE death signatures by vaccine and coadministered vaccines, pointing to possible overlapping etiologies worthy of further investigation. Immediate onset of fall AEs has been previously reported [24].

5. Conclusions

Informed consent considers risks versus benefits for vaccines and coadministered vaccines. This study identifies clear safety signals that increase with age for death associated with specific vaccines. Multiple safety signals associated with increased mortality risks were identified and are worthy of follow-up studies.

The risk of falling within two days post-immunization increases with age. Reiterating: “Avoidance of activities like driving, operating heavy machinery, with increased risks of falling, etc., for one to two days following immunization provides an opportunity to reduce the frequency of falls, injuries, and other rare accidents” [24].