Introduction: The unique characteristics of the U.S. Armed Forces, with frequent deployments exposing personnel to diverse infectious threats, result in an exceptionally highly vaccinated population. While various vaccines are administered concurrently, the impact of multiple vaccinations on health outcomes remains uncertain. This study investigates the association between concurrent vaccinations and medical encounters in service members, considering demographic variables and specific medical symptoms and the types of vaccines administered.

Data and methods: Utilizing a population-based prospective design, we tracked a cohort of active-duty service members from 2004 to 2014, with complete vaccine records. Concurrent vaccinations were defined as receiving ≥1 vaccine within a 7-day period. Logistic and Poisson regression analyses were employed, controlling for gender, age, race, service, military grade, and deployment status. The top 12 medical encounters and 12 commonly used vaccines were studied.

Results: Demographic analysis revealed a well-matched distribution between single and multiple vaccine groups. Both regressions showed that for concurrent vaccines numbering less than 4, adverse effects were minimal, but risks increased with 5 or more vaccines. However, the effects on medical encounters varied across individual symptoms and types of vaccines, with 5 or more vaccines showed higher risks for medical encounters.

Conclusion: Concurrent vaccine injection appears safe, particularly with 4 or fewer vaccines. Risks increase with a higher number of vaccines. The study

contributes valuable insights into the safety of concurrent vaccinations, emphasizing the need for cautious administration in specific scenarios.

Levin LI, Doung S, Li Y (2024) Concurrent Vaccinations and the Enigma of Adverse Effects among Military Service Members Over 10 Years Records. Ann Vaccines Immunization 9(1): 1025.

The COVID-19 pandemic has confirmed that vaccination is highly effective, and a variety of vaccines are available and recommended to against influenza (annually), pneumococcal or meningococcal disease, herpes zoster, diphtheria, tetanus, pertussis, and human papillomavirus etc [1]. As a result, multiple vaccinations are administered during a single once visit or in close succession. The active components of the U.S. Armed Forces are unique in being an exceptionally highly vaccinated population, with several vaccines including biodefense vaccinations often administered concurrently. This is due to multiple deployments to parts of the world, where personnel are expected to encounter various infectious disease threats, including exposure to agents used as biological weapons [2-5]. In particular, anthrax, smallpox, typhoid, and yellow fever vaccines are administered to large proportions of deployed military personnel [6], but not often given to the general civilian population. It is, therefore, likely that these vaccines are administered for the first time while individuals are on active duty. Smallpox and yellow fever are live attenuated viral vaccines, which would be expected to drive primarily a Th1 dominant response, whereas anthrax and typhoid vaccines are inactivated bacterial vaccines, which would be expected to be associated with a Th17 pro-inflammatory response [7,8]. Bacterial vaccines, such as anthrax would be expected to be more potent, broader immune stimulators than other vaccines, such as viral vaccines based on recombinant proteins. Often multiple vaccinations are administered on the same day for logistical reasons.2 It increases the complexity of assessing vaccine safety. Individual vaccines are assumed to have no other effect than protection against the targeted pathogen, but vaccines also have nonspecific and interactive effects, the outcomes of which can be beneficial or harmful. To date, few studies have determined the impact of vaccination schedules on overall health and the findings were complex.

Payne DC, et al. [9] did not find an association comparing hospitalization rates before and after the administration of concurrent vaccinations among a selected cohort of military personnel who were not deployed. Broderick KE, et al. [10] compared medical encounter data pre-and post-vaccination in a small study of military personnel who received inactivated polio vaccine in combination with other vaccines and reported no association between concurrent vaccinations and subsequent medical encounters. In Börner N, et al. [11] study the overall frequency of systemic side effects among 1183 German travelers increased with the number of simultaneously administered vaccines (36.7% for two, 40.3% for three, and 50.0% for more than three), the subjective rating by the study participants showed an excellent tolerability of multiple vaccinations before travel. Among 399 Japanese travelers, 257 were received up to five simultaneous vaccines against either hepatitis A, hepatitis B, rabies, Japanese encephalitis, diphtheria, tetanus, measles, mumps, and poliomyelitis, the overall rate of adverse events was 26.3%, significantly higher than those single vaccine receivers [12]. The balance of the risks and benefits from mass vaccination therefore remains uncertain and limited information is available to determine whether exposure to concurrent vaccinations is associated with an increased incidence of harmful medical encounters. Among a group of Chinese travelers, 772 participants received a total of 2,533 vaccine doses, with 49.6% reporting adverse reactions within seven days following vaccination. Of these, 39.8% (307/772) experienced local reactions, and 20.2% (156/772) experienced systemic reactions [13].

This study uses a prospective design to determine if there is an increased rate of medical encounters among service members associated with concurrent vaccination, by comparing the rates of such encounters. The eligible study cohort was assembled by the Armed Forces Health Surveillance Branch (AFHSB), with relevant data elements, including medical encounter data and vaccination records, retrieved through queries of the Defense Medical Surveillance System (DMSS), managed by the AFHSB. The study included data on over 80 different types of medical encounters, such as back pain, pharyngitis, headache, and dyspnea, as well as data on dozens of vaccines, including influenza, typhoid, hepatitis A, and hepatitis B, collected from over 336,000 active service members.

Using this extensive and unique dataset, various statistical analyses were conducted to examine the association between concurrent vaccination and medical encounters. The results enhance the understanding of vaccine pathophysiology, potential adverse effects, and overall vaccine safety.

This study employed a population-based prospective design, tracking a cohort over time to examine the subsequent number and types of medical encounters in both inpatient and outpatient settings. Pre-vaccine exposure and post-vaccination exposure periods following the administration of concurrent vaccinations were defined. All active component service members with complete vaccine records and medical encounters were included in the study population. Specifically, individuals who had been on active duty for at least one year from January 1, 2004, to December 31, 2014, and received at least one vaccination were considered.

Concurrent vaccinations were defined as the receipt of ≥1 vaccination within a 7-day period Medical encounter data and hospitalizations within 14 days before and after vaccination were collected to determine medical encounter visits and hospitalizations. Subjects were divided into two groups: those with only one vaccine as the single vaccine group and a randomly selected multiple vaccine group matched by vaccine date, gender, age, branch of service, military grade, and race/ ethnicity.

Descriptive analyses were initially conducted to obtain basic data information. Subsequently, logistic and Poisson regression analyses were applied, with the primary predictor being the vaccine number categorized as 2, 3, 4, 5, and 6 & above, compared with the single vaccine. Due to the rarity of events for specific medical encounters, categories were modified if the data did not allow parameter estimation for the top level (e.g., 6 and above modified to 5 and above). Control factors included gender, age, race, service, military grade, and deployment status.

Medical encounter information was analyzed for all medical encounters collectively and specific categories. The top 12 related symptoms with higher counts among both single and multiple vaccines were selected as outcomes. Subjects in different symptom analyses were not mutually exclusive, as the same individual could experience different symptoms.

Logistic regression was employed to assess medical status (yes or no), indicating whether an individual had at least one symptom in the 14 days following vaccination. Poisson regression was used for the total medical encounter days within 14 days, defined as the day an individual had any medical encounter or the medical encounter day of a specified diagnosis if they experienced a particular medical encounter.

Medical  encounters  included  both  inpatient  and outpatient visits, and diagnoses were based on 3-digit International Classification of Diseases, 9th Revision (ICD- 9) codes. Additionally, the top 12 commonly used vaccines, characterized by a large data size and allowing multiple vaccine numbers as predictors, were further categorized. For specified symptom or specified vaccine, data within single and multiple vaccines were also matched by vaccine date, gender, age, branch of service, military grade, and race/ethnicity for comprehensive analysis.

Table 1 indicates a well-matched demographic distribution between single vaccine and multiple vaccine groups.

Table 1: The counts and percentage of single vaccine and matched concurrent vaccine groups.

Any minor age differences by categories resulted from matching individuals within a year. Despite large sample size, the study demonstrates valuable estimates. The primary aim is to assess medical encounter risks by comparing single and multiple vaccines. The outcome is medical encounters within 14 days post-vaccination, with the vaccine number as the main exposure. Approximately 8.95% of single vaccine recipients and 7.11% of multiple vaccine recipients experienced at least one medical encounter within the specified timeframe. The average medical encounter days were 0.14 and 0.11 for single and multiple vaccine groups, respectively.

Two analyses were conducted: i. Logistic regression assessed if subjects had at least one medical encounter within two weeks, considering vaccine number, sex, age, vaccine year, and deployment status as co-factors in 

the regression. ii. Poisson regression evaluated medical encounter days, with co-factors of vaccine counts, sex, age, grade, service, race, vaccine year, and deployment.

Table 2 presents results for combined medical encounters and the top 11 causes following vaccination. Vaccine number was a major predictor, categorized by actual numbers were reported. Five models were applied based on vaccine count categories, and the Akaike information criterion guided model selection.

Table 2: The concurrent vaccine effects on medical encounters.

Overall findings suggest that for all medical symptoms, having fewer than 4 concurrent vaccines had a protective effect. Five or more concurrent vaccines might pose higher risks based on both logistic and Poisson regression analyses.

The results generated from two types of the regression modeling were consistent. Individual symptom risks varied, but generally supported these conclusions.

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1. For any medical symptom, the OR (logistic regression) increased from 0.8 (p<0.001 Vaccine Number (VN)=2 or 3) to 1.0(NS, VN=4), 1.4 (p<0.01, VN=5) and 1.6 (p<0.01, VN>5); similar but a little less estimation of RR (Poisson Regression), but a little less were observed.
2. In the following 14 days, limb pain occurred in about 2.4% of the population. Injection of 4 or more vaccines increased the risk for encounter days. But they are not significant for OR and significant for RR.
3. Pharyngitis risk increased with concurrent vaccines. All estimations were greater than one, and significant. When injecting concurrent 4 or more vaccines, the high risks were significant for both OR and RR.
4. Headache risk increased with the number of vaccines but did not reach significance.
5. Dyspnea/wheezing risk increased with number of vaccines but did not reach significance.
6. Nausea/vomiting risk doubled with 4 or more concurrent vaccines, which were significant.
7. Myalgia risks were negatively (less than 1) except for VN>=5, OR=2.04, not significant.
8. For dermatitis, most estimates of OR and RR were less than 1, except for OR=1.06, (VN≥5), not significant.
9. For cough, most estimates of OR and RR were less than 1, except for VN≥5, RR=2.04, RR=1.29, both were not significant.
10. For Diarrhea, all estimations were around 1, but not significant.
11. For Dizziness, VN≥4, OR and RR were greater than 1, but they are not significant.
12. For malaise/fatigue did not exhibit significant risks, all estimates were less than 1.

Table 3 

Table 3: The commonly injected vaccines among the military services.

displays the top 10 vaccines, with consistent percentage distributions between single and multiple vaccine groups. Only minor difference in order, except for Meningococcal and Influenza, unspecified in top 10 for both groups.

According to the counting distribution of frequently used vaccines from the data and literature. Twelve different types of vaccines were selected for further study, the selected vaccine was injected for both matched cases and controls. The medical encounter status and days were used as outcomes. Odds ratio and rate ratios were estimated by logistic regression and Poisson regression. Table 4 shows the results.

Table 4: Concurrent vaccine effects on overall medical encounters by vaccine type.

The investigation into concurrent vaccine injections involved an extensive study with a large sample size, encompassing all active service personnel over a ten- year period with a minimum of one year of service and at least one vaccination. These individuals were compared with matched controls totaling 168,410 in each group. Descriptive analyses, as well as multiple logistic regression and Poisson regression, were applied. Results indicated that for concurrent vaccines numbering less than 4, fewer adverse effects were observed across various medical encounters and individual symptoms, including Pain in Limb, Headache, Dyspnea/wheezing, Nausea/Vomiting  Myalgia, Dermatitis, Cough, Dizziness, and Malaise/ Fatigue. Some findings reached high significance. However, when 5 or more concurrent vaccines were administered, a significant increase in the risk of overall medical encounters, Pharyngitis and Nausea/Vomiting were noted.

The examination of concurrent vaccines, specifically 12 commonly used vaccines, revealed no significant risks overall for all individual vaccines, except for Meningococci. Intriguingly, injecting Meningococci concurrently resulted in odds ratios and rate risks greater than 1, with high significance for vaccine numbers exceeding 3. For three vaccines injected concurrently, OR=2 (p=0.08) and RR=3.7 (p<0.0001).

In summary, concurrent vaccine injection appears to be safe, particularly when the total vaccine number is 4 or less. However, the risk increases with a higher number of vaccines.

This study affirms the safety of concurrent vaccines when compared to single vaccines, aligning with findings from existing literature. Surveys assessing vaccination attitudes among returning troops and studies on specific vaccines, such as anthrax and smallpox, within military populations corroborate our results. Notably, our study adds a unique contribution by examining a matched sample of all military adults, controlling for sex, race, and age.

Comparisons with other studies reveal complexity in findings. While some studies showed no association between concurrent vaccinations and subsequent medical encounters, others reported increased systemic side effects with the number of simultaneously administered vaccines. Our study distinguishes itself by its matched design, controlling for various factors, and relying on accurate professional medical records for diagnoses, minimizing bias, self-reported inaccuracies between single and concurrent vaccine groups.

The analysis of medical encounters based on pre- medical status within 14 days before vaccination was also performed. Overall, about 9% of single vaccine personnels and 7 % of multi vaccine personnels had at least one medical encounter within 14 days after vaccine and 8% of those who receive single vaccine and 6% of those who received multiple vaccines within 14 days before vaccine injection. The change is consistent. Using overall medical encounter status as outcome, the OR by logistic regression with Generalized Estimating Equation (GEE) approach were 0.85 (VN=2), 0.77 (VN=3), 0.99(VN=4), 1.12 (VN=5) and 1.51 (VN=5), which were almost the same as those in Table 2. The premedical status was rare event, and its effect were weak.

In conclusion, this study contributes valuable insights into the safety of concurrent vaccines, shedding light on the importance of careful consideration when administering multiple vaccines simultaneously.

The authors would like to express their sincere gratitude to the Armed Forces Health Surveillance Branch for assembling and creating the analytical dataset used in this study, and to the Defense Health Agency for sponsoring the research. Special thanks are extended to Col. Kelvin Tylor for his role in identifying and selecting the pool of vaccines and vaccine-related symptoms. The first two authors also acknowledge partial funding support from the Global Emerging Infections Surveillance program.

Conceptualization; Proposal and Method, L.L and Y.Li; Algorithms and Data Analysis,.Y. Li and S. D; Writing—Y. Li; Review & editing, Y.L. and S.D.

1. Vaccine schedules in all countries in the EU/EEA. ECDC. 2021.
2. Grabenstein JD, Pittman PR, Greenwood JT, Engler RJ. Immunization to protect the US armed forces: Heritage, current practice, and prospects. Epidemiol Rev. 2006; 28: 3-26.
3. Grabenstein JD, Winkenwerder W Jr. Bioterrorism and compulsory vaccination: United States continues vaccinating to keep troops healthy. BMJ. 2004; 329: 977.
4. Ho ZJ, Hwang YF, Lee JM. Emerging and re-emerging infectious diseases: Challenges and opportunities for militaries. Mil Med Res. 2014; 1: 21.
5. Murray CK, Yun HC, Markelz AE, Okulicz JF, Vento TJ, Burgess TH, et al. Operation united assistance: Infectious disease threats to deployed military personnel. Mil Med. 2015; 180: 626-651.
6. Immunizations and chemoprophylaxis for the prevention of infectious diseases. Army Regulation 40–562 BUMEDINST 6230.15B AFI 48–110_IP CG COMDTINST M6230.4G. 2013.
7. Cieslak TJ, Christopher GW, Kortepeter MG, Rowe JR, Pavlin JA, Culpepper RC, et al. Immunization against potential biological warfare agents. Clin Infect Dis. 2000; 30: 843-850.
8. Thakur A, Pedersen LE, Jungersen G. Immune markers and correlates of protection for vaccine induced immune responses. Vaccine. 2012; 30: 4907-4920.
9. Payne DC, Aranas A, McNeil MM, Duderstadt S, Rose CE Jr. Concurrent vaccinations and U.S. military hospitalizations. Ann Epidemiol. 2007; 17: 697-703.
10. Trevor RFS , Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nature Communications. 2020; 11: Article number: 2601.
11. Börner N, Mühlberger N, Jelinek T. Tolerability of multiple vaccinations in travel medicine. J Travel Med. 2003; 10: 112-116.
12. Mizuno Y, Kano S, Urashima M, Genka I, Kanagawa S, Kudo K. Simultaneous vaccination in Japanese travelers. Travel Med Infect Dis. 2007; 5: 85-89.
13. Hua L, Hongtao H, Shunqin W, Jinping G, Jiandong C, Zhaoliang L, et al. Simultaneous vaccination of Chinese applicants for a United States immigrant visa. Travel Med Infect Dis. 2008; 6: 130-136.