Neonatal, Infant, and Under Age Five Vaccine Doses Routinely Given in Developed Nations and Their Association With Mortality Rates.

Introduction In 2011, using 2009 data, we published a study demonstrating that among the most highly developed nations, those requiring the most vaccine doses for their infants tended to have the least favorable infant mortality rates (r = 0.70, p < .0001). Twelve years later, we replicated our original study using 2019 data. Linear regression analysis corroborated the positive trend reported in our initial paper (r = 0.45; p < .002). Herein, we broaden our analyses to consider the effect of vaccines on neonatal and under age five mortality rates.  Objective We performed several investigations to explore potential relationships between the number of early childhood vaccine doses required by nations and their neonatal, infant, and under age five mortality rates. Methods In this ecological study, we conducted linear regression analyses of neonatal, infant, and under age five vaccine doses required by nations and their neonatal, infant, and under age five mortality rates. All analyses were based on 2019 and 2021 data. We also stratified nations by the number of neonatal vaccine doses required and conducted a one-way ANOVA test and a post hoc Tukey-Kramer test to determine if there were statistically significant differences in the group mean neonatal, infant, and under age five mortality rates of nations that administered zero, one, or two neonatal vaccine doses. Results Linear regression analyses of neonatal vaccine doses required by nations in our 2021 dataset yielded statistically significant positive correlations to rates of neonatal mortality (r = 0.34, p = .017), infant mortality (r = 0.46, p = .0008), and under age five mortality (r = 0.48, p = .0004). Similar results were reported using 2019 data. Utilizing 2021 data, a post hoc Tukey-Kramer test indicated a statistically significant pairwise difference between the mean neonatal mortality rates, mean infant mortality rates, and mean under age five mortality rates of nations requiring zero vs. two neonatal vaccine doses. There was a statistically significant difference of 1.28 deaths per 1000 live births (p < .002) between the mean infant mortality rates among nations that did not give their neonates any vaccine doses and those that required two vaccine doses. Using 2019 and 2021 data, 17 of 18 analyses (12 bivariate linear regressions and six ANOVA and Tukey-Kramer tests) achieved statistical significance and corroborated the findings reported in our original study of a positive association between the number of vaccine doses required by developed nations and their infant mortality rates. Conclusions There are statistically significant positive correlations between mortality rates of developed nations and the number of early childhood vaccine doses that are routinely given. Further investigations of the hypotheses generated by this study are recommended to confirm that current vaccination schedules are achieving their intended objectives.

Reaffirming a Positive Correlation Between Number of Vaccine Doses and Infant Mortality Rates: A Response to Critics.

Introduction In 2011, we published a study that found a counterintuitive, positive correlation, r = 0.70 (p < .0001), demonstrating that among the most highly developed nations (n = 30), those that require more vaccines for their infants tend to have higher infant mortality rates (IMRs). Critics of the paper recently claimed that this finding is due to "inappropriate data exclusion," i.e., the failure to analyze the "full dataset" of all 185 nations. Objective In the present study, we examine various claims postulated by these critics and the validity of their scientific methods, and we perform several investigations to assess the reliability of our original findings. Methods The critics select 185 nations and use linear regression to report a correlation between the number of vaccine doses and IMRs. They also perform multiple linear regression analyses of the Human Development Index (HDI) vs. IMR with additional predictors and investigate IMR vs. percentage vaccination rates for eight different vaccines. We perform odds ratio, sensitivity, and replication analyses. Results The critics' reanalysis combines 185 developed and Third World nations that have varying rates of vaccination and socioeconomic disparities. Despite the presence of inherent confounding variables, a small, statistically significant positive correlation of r = 0.16 (p < .03) is reported that corroborates the positive trend in our study. Multiple linear regression analyses report high correlations between IMR and HDI, but the number of vaccine doses as an additional predictor is not statistically significant. This finding is a likely consequence of known misclassification errors in HDI. Linear regression of IMR as a function of percentage vaccination rates reports statistically significant inverse correlations for 7 of 8 vaccines. However, several anomalies in the scatter plots of the data suggest that the chosen linear model is problematic. Our odds ratio analysis conducted on the original dataset controlled for several variables. None of these variables lowered the correlation below 0.62, thus robustly confirming our findings. Our sensitivity analysis reported statistically significant positive correlations between the number of vaccine doses and IMR when we expanded our original analysis from the top 30 to the 46 nations with the best IMRs. Additionally, a replication of our original study using updated 2019 data corroborated the trend we found in our first paper (r = 0.45, p = .002). Conclusions A positive correlation between the number of vaccine doses and IMRs is detectable in the most highly developed nations but attenuated in the background noise of nations with heterogeneous socioeconomic variables that contribute to high rates of infant mortality, such as malnutrition, poverty, and substandard health care.

Examples of Outcome Reporting Bias in Vaccine Studies: Illustrating How Perpetuating Medical Consensus Can Impede Progress in Public Health.

INTRODUCTION: Outcome reporting bias in vaccine studies is a widespread problem among all researchers who have a tendency to report selective results and conclusions that support their beliefs and values or those of sponsoring agencies. Especially during the COVID-19 pandemic, this bias surfaced through the unprecedented proliferation of conflicting vaccine studies. Many researchers strongly recommend and report on the safety and effectiveness of the COVID-19 vaccine. Those researchers who embrace the COVID-19 vaccine and vaccines, in general, are often dismissive of other researchers who present views that differ from medical orthodoxy and oppose medical consensus. METHODS: The aim of this analysis is to critically evaluate seven vaccine studies using qualitative and/or quantitative approaches to identify outcome reporting bias and assess its potential impact on the stated conclusions that align with medical consensus. Four studies claim to have found no association between autism and (a) blood levels of mercury, (b) measles, mumps, and rubella (MMR) vaccine, and (c) thimerosal-containing vaccines. Three other studies claim no association exists between infant mortality rate and the number of vaccine doses, universal varicella vaccination and herpes zoster, and pandemic influenza vaccines and fetal losses. RESULTS: The presence of outcome reporting bias and independent reanalysis demonstrated an impact on both the direction and magnitude of the observed effect - raising questions concerning the robustness of the original study design and conclusions and challenging the current medical consensus. Medical consensus has exonerated vaccines as having any causal relationship to autism spectrum disorders (ASDs), yet no other reasonable cause has been proposed. Medical consensus attributes significant ASD increases to better case ascertainment and broadened clinical diagnosis. According to 2018 data, an estimated 1 in 44 eight-year-olds has been identified with ASD. From 1990 to 2019, there have been an estimated two million new cases of ASD in the US, with lifetime social costs exceeding $7 trillion (in 2019 dollars). Can perpetuating medical consensus impede the advancement of public health? Or has it already done so? CONCLUSIONS:  Conflicts of interest (e.g., financial) that abound between health regulatory agencies and the pharmaceutical industry impact what is ultimately reckoned as medical consensus. Outcome reporting bias that is inherent to all researchers to some degree, obscures medical and scientific truth. Advancement of public health requires that researchers have integrity and an openness and willingness to collaborate to resolve contradictory findings. In fact, it is usually through meticulous, rigorous, scientific investigation of contradictory findings that medical science has advanced and contributed to improvements in public health - since medical consensus and orthodoxy can be incorrect.

Correction: Insights on the Impact of External and Internal Boosting on Varicella-Zoster Virus Reactivation Based on Evidence From the First Decade of the United States Universal Varicella Vaccination Program.

[This corrects the article DOI: 10.7759/cureus.16963.].

Insights on the Impact of External and Internal Boosting on Varicella-Zoster Virus Reactivation Based on Evidence From the First Decade of the United States Universal Varicella Vaccination Program.

Since the licensure of the varicella vaccine in the United States in 1995 and the implementation of the universal varicella vaccination program, varicella infection rates, and associated morbidity and mortality rates have decreased. However, controversy exists over whether universal vaccination has resulted in an increased incidence of herpes zoster (HZ). In 1965, Dr. Hope-Simpson hypothesized that exogenous exposures to the wild-type varicella-zoster virus (wt-VZV) provide immune boosts that inhibit HZ; therefore, reducing the amount of circulating wt-VZV may have the negative effect of increasing the incidence of HZ. A historical review of data from the Centers for Disease Control and Prevention-sponsored Antelope Valley Varicella Active Surveillance Project, along with other studies, is provided to investigate the exogenous boosting hypothesis in the first decade post-vaccine licensure. These data indicated that adoption of universal varicella vaccination led to (1) significant HZ incidence rate increases among children, adolescents, and adults with a history of wild-type varicella and (2) decline in varicella vaccine efficacy after the initial post-licensure period. These effects were likely due to reduced exogenous exposures from children shedding wt-VZV. Appropriate methodologies for ongoing research are also discussed, both in studies during the first decade post-licensure and more recent work.

Infant mortality rates regressed against number of vaccine doses routinely given: is there a biochemical or synergistic toxicity?

The infant mortality rate (IMR) is one of the most important indicators of the socio-economic well-being and public health conditions of a country. The US childhood immunization schedule specifies 26 vaccine doses for infants aged less than 1 year--the most in the world--yet 33 nations have lower IMRs. Using linear regression, the immunization schedules of these 34 nations were examined and a correlation coefficient of r = 0.70 (p < 0.0001) was found between IMRs and the number of vaccine doses routinely given to infants. Nations were also grouped into five different vaccine dose ranges: 12-14, 15-17, 18-20, 21-23, and 24-26. The mean IMRs of all nations within each group were then calculated. Linear regression analysis of unweighted mean IMRs showed a high statistically significant correlation between increasing number of vaccine doses and increasing infant mortality rates, with r = 0.992 (p = 0.0009). Using the Tukey-Kramer test, statistically significant differences in mean IMRs were found between nations giving 12-14 vaccine doses and those giving 21-23, and 24-26 doses. A closer inspection of correlations between vaccine doses, biochemical or synergistic toxicity, and IMRs is essential.

The case against universal varicella vaccination.

In 1995, the United States became the first country to implement a Universal Varicella Vaccination Program. Several questions remain: Is the varicella (chickenpox) vaccine needed? Is it cost effective as a routine immunization for all susceptible children? Or is it more beneficial for the disease to remain endemic so that adults may receive periodic exogenous exposures (boosts) that help suppress the reactivation of herpes zoster (shingles). In addition, as vaccination coverage becomes widespread, does loss of immunologic boosting cause a decline in vaccine efficacy and result in a reduced period of immunity? Scientific literature regarding safety of the varicella vaccine and its associated cost-benefit analysis have often reported optimistic evaluations based on ideal assumptions. Deleterious outcomes and their associated costs must be included when making a circumspect assessment of the Universal Varicella Vaccination Program.

Universal varicella vaccination: efficacy trends and effect on herpes zoster.

In 1995, the Varicella Active Surveillance Project (VASP) was established in Antelope Valley (California), a geographically distinct high-desert community of 300,000 residents, as one of three sites in the nation in a cooperative agreement with the Centers for Disease Control and Prevention (CDC) to collect baseline demographic and clinical data and to monitor trends in varicella (chickenpox) following introduction of varicella vaccine. Herpes zoster (shingles) was added to the active surveillance January 1, 2000. The universal varicella program has proven effective in terms of reducing the number of reported verified varicella cases by 85%, from 2,934 in 1995 to 412 in 2002. Prior to this dramatic reduction, immunologic boosting due to exogenous exposures to wild-type varicella-zoster virus (VZV) in the community (1) caused mean serum anti-VZV levels among vaccines to increase with time after vaccination and (2) served as a mechanism that helped suppress the reactivation of herpes zoster (HZ), especially among individuals with a previous history of wild-type varicella. That immunologic boosting might play a significant role in both varicella and the closely related HZ epidemiology is evidenced by (1) a decline in vaccine efficacy by over 20%, from 95.7% (95% C.I., 82.7% to 98.9%) in 1999 to 73.9% (95% C.I., 57.9% to 83.8%) in 2001 and (2) an unexpectedly high cumulative (2000 to 2003) true incidence rate of 223 (95% C.I. 180-273) per 100,000 person-years (p-y) among children <10 years old with a previous history of varicella. Because capture-recapture methods demonstrate a likely lower bound of 50% underreporting, the actual rate is likely double or 446 per 100,000 p-y, approaching the HZ rate reported among older adults. Other recent studies based on VASP data have mitigated against discovery of the above trends that challenge several initial assumptions inherent to the universal varicella program, namely, (1) a single dose confers long-term immunity and (2) there is no immunologically mediated link between varicella and HZ incidence. As vaccinated children replace those with a prior history of wild-type varicella in the <10 age group, increasing HZ incidence among this cohort will be of less concern in the near future. However, previous scientific studies, including the present preliminary results from active surveillance indicate that HZ may be increasing among adults. It may be difficult to design booster interventions that are cost-effective and meet or exceed the level of protection provided by immunologic boosting that existed naturally in the community in the prelicensure era.

Varicella susceptibility and incidence of herpes zoster among children and adolescents in a community under active surveillance.

Licensure of varicella vaccine by the US Food and Drug Administration in March 1995 has given rise to concerns that include a potential shift in varicella incidence to susceptible adults and increase in herpes zoster (HZ) incidence. Baseline values prior to widespread vaccination were obtained through distribution of an adolescent survey to all 13 public middle (seventh and eighth grade) schools in the Antelope Valley, CA health district. Based on 4216 respondents aged 10-14 years, varicella susceptibility is 7.7% (95% CI, 6.9-8.5%) and true cumulative (1987-2000) HZ incidence rate is 133 per 100,000 person-years (95% CI, 95-182 per 100,000 person-years).

Varicella disease after introduction of varicella vaccine in the United States, 1995-2000.

CONTEXT: Before licensure of varicella vaccine in 1995, varicella was a universal childhood disease in the United States, causing 4 million cases, 11,000 hospitalizations, and 100 deaths every year. OBJECTIVE: To examine population-based disease surveillance data in 3 communities to document the impact of the varicella vaccination program. DESIGN, SETTING, AND SUBJECTS: Active surveillance for varicella conducted among the populations of Antelope Valley, Calif; Travis County, Tex; and West Philadelphia, Pa; from January 1, 1995, to December 31, 2000. Reporting sites included child care centers, schools, universities, physicians, public health clinics, hospitals, emergency departments, and households. MAIN OUTCOME MEASURES: Trends in number and rate of varicella cases and hospitalizations; varicella vaccine coverage. RESULTS: From 1995 through 1998, in each surveillance area, the number of verified varicella cases varied from year to year with marked springtime seasonality. In 1999, the number and rates of varicella cases and hospitalizations declined markedly. From 1995 through 2000, in Antelope Valley, Travis County, and West Philadelphia, varicella cases declined 71%, 84%, and 79%, respectively. Cases declined to the greatest extent among children aged 1 to 4 years, but cases declined in all age groups, including infants and adults. In the combined 3 surveillance areas, hospitalizations due to varicella declined from a range of 2.7 to 4.2 per 100,000 population in 1995 through 1998 to 0.6 and 1.5 per 100,000 population in 1999 and 2000, respectively (P =.15). By 2000, vaccine coverage among children aged 19 to 35 months was 82.1%, 73.6%, and 83.8% in Los Angeles County, Texas, and Philadelphia County, respectively. CONCLUSIONS: Varicella disease has declined dramatically in surveillance areas with moderate vaccine coverage. Continued implementation of existing vaccine policies should lead to further reductions of varicella disease in these communities and throughout the United States.