IMMUNIZATIONS

Vaccine Definition - biological product used to induce a protective immune response to an infection that would cause disease with exposure to the infection (Nat Rev Immunol. 2021; 21(2):83-100).

Vaccination Technology - historic breakthroughs (Desmond A and Offit PA. Perspective article. N Engl J Med. 2021. 384. 1081-1083)

  • First advance - 1796 (Edward Jenner): Use of an animal virus (cowpox) as a vaccine against disease caused by a human virus (smallpox)

    • Rotavirus vaccine is derived in part from a bovine strain of the virus

  • Second advance - 1885 (Louis Pasteur): Prepare a vaccine using physically or chemically inactivated viruses (rabies) against disease caused by the virus

    • Influenza vaccine in the 1940’s, polio vaccine in the 1950’s, hepatitis A vaccine in 1991 derived from inactivated viruses

  • Third advance - 1937 (Max Theiler): Attenuate the virulence of a virus (yellow fever) by means of serial passage in nonhuman cells (mouse and chicken embryos)

    • Polio vaccine in the 1960’s, measles vaccine in 1963, mumps vaccine in 1967, rubella vaccine in 1969, varicella vaccine in 1995, rotavirus vaccine in 2008

  • Fourth advance - 1980 (Richard Mulligan and Paul Berg): Recombinant DNA technology

    • Hepatitis B virus vaccine in 1986, HPV vaccine in 2006, influenza vaccine in 2013

  • Fifth advance - 2020: mRNA technology

    • Covid vaccines (Pfizer and Moderna)

Broad categorization of vaccines historically - live (attenuated) or non-live (inactivated)

  • Inactivated vaccines do not produce as strong an immune response as live vaccines

  • Adjuvants (see section of this web page just below) are added to inactivated vaccines to increase the immunogenicity of the vaccine

Nonspecific beneficial effects of vaccines (Jacob Schor, ND, Townsend Letter. October 2014. Pages 90-93)

  • Observational data suggest that live attenuated vaccines (BCG, measles, smallpox) offer protection from a wide variety of infections. Specifically, data shows that measles vaccination in developing countries is associated with a 1/3 drop in death rate, mainly by protecting against pneumonia, sepsis and diarrhea (Ugeskr Laeger. 1996. 158. 5944-5948; Int J Epidemiol. 2003. 32. 106-116).

  • In contrast, vaccines composed only of “dead” toxoids (DPT vaccine) have a neutral or even negative nonspecific effect. However, administering measles vaccine chronologically just after DPT may offer nonspecific protection. In a RCT in Guinea-Bissau, an initial dose of measles vaccine at 4.5 months, just after completion of DPT, and a second dose at 9 months, was associated with a 30% decrease in all-cause mortality up to 3 years of age, with less than 5% of the reduction in mortality attributable to measles prevention (BMJ. 2010. 341. c6495).

  • Vaccination with both BCG and smallpox vaccine is associated with a 36% reduction of melanoma risk (J Invest Dermatol. 2002. 119. 570-575); vaccination with yellow fever vaccine is associated with a 74% reduction in melanoma risk (Vaccine. 2009. 27. 588-591). The mechanism of protection is uncertain.

Cost effectiveness of vaccination

  • It has been estimated that immunization with 7 of the 12 routinely recommended childhood vaccines prevents an estimated 33,000 deaths and 14 million new cases of disease in every birth cohort, saves $10 billion in direct costs in each birth cohort, and saves society an additional $33 billion in costs that include disability and lost productivity (Arch Pediatr Adolesc Med. 2005. 159. 1136-1144).

Components of a vaccine (info based on vaccine manufacturers’ product inserts)

  • Antigens – main component

    • Viruses (influenza, polio, measles, etc.)

    • Bacteria (Pneumococcus, Bordetella pertussis)

    • Toxoids (Tetanus toxoid)

  • Growth mediums

    • Chick embryo fibroblasts

    • Chick cell kidneys

    • Mouse brains

    • Monkey kidney

    • Human diploid cells cultured from aborted human fetuses (MRC-5, RA 27/3, WI-38)

  • Adjuvants – use to enhance the immune response

    • Aluminum salts - the dosage in vaccines is based on research determination of the dose to maximize production of antibody titers; research on safety, especially in infants and regarding the safety of injected aluminum (versus ingested aluminum in food) is limited; at a cellular level, aluminum may have effects on the endoplasmic reticulum and Golgi apparatus, and may impair mitochondrial function.

      • Babies following the CDC vaccination schedule are injected with 250 mcg of aluminum at birth in conjunction with the hepatitis vaccine, as much as 1475 mcg of aluminum at the 12 month or 15 month checkup, and a total of nearly 5000 mcg (5 mg) by 18 months of age

      • Aluminum has been associated with neurotoxicity (N Engl J Med. 1997. 336. 1557-1562).

    • Squalene (was used in some H1N1 vaccines)

    • New adjuvants in development in 2021 - liposome-based or oil in water emulsions

  • Preservatives – used to prevent microbial contamination of vaccines

    • Thimerosal (ethyl mercury) – possible neurotoxin

    • Benzonium chloride – possible endocrine toxin

    • 2 phenoxyethanol – similar in chemical structure to antifreeze, possible reproductive toxin

    • Phenol – possible dermatologic, hematologic, hepatic, neurological, reproductive, and respiratory toxic effects

  • Stabilizers – inhibit chemical reactions and prevent vaccine components from separating or sticking to the vial

    • Fetal bovine serum

    • Monosodiumglutamate (MSG)

    • Human serum albumin

    • Porcine gelatin

  • Antibiotics – may be added to prevent bacterial growth during vaccine production and storage

    • Neomycin

    • Polymyxin B

    • Streptomycin

  • Additives (buffers, diluents, emulsifiers, excipients, residuals, solvents)

    • Ammonium sulfate

    • Egg protein and yeast

    • Glycerin

    • Hydrochloric acid

    • Polysorbate 80 (Tween 80)

    • Potassium chloride

    • Sodium borate

    • Sodium chloride

    • Sodium hydroxide

  • Inactivating chemicals – kill unwanted viruses and bacteria in the vaccine

    • Formaldehyde – a known carcinogen

    • Glutaraldehyde – possible toxin

    • Polyoxyethylene – possible endocrine toxin

  • Contaminants – viruses such as the SV-40 vaccine found in early polio vaccines and HIV discovered in early hepatitis B vaccines

Advisory Committee on Immunization Practices (ACIP) [Viewpoint. JAMA. 2019. 321. 341-342]

  • Established in 1964 by the Surgeon General – goal is to examine the science and ensure best use of vaccines in the US. Provides guidance to the CDC and Secretary of HHS.

  • Uses the GRADE process to determine the quality of the evidence regarding benefits and harms of vaccines, and since 2018 also uses the Evidence to Recommendations framework to consider the burden and public health importance of the disease.

  • Committee consists of 14 immunization experts and consumer advocate – meetings are public.

  • NOTE role of the FDA is to license vaccines.

 Vaccine Injury Compensation Program (VICP) [Viewpoint. JAMA. 2019. 321. 343-344]

  • Established in 1986 when Congress passed the National Vaccine Injury Act.

  • This program is a no-fault alternative for resolving vaccine injury cases

  • Multifold goals

    • Compensate recipients and families alleged to have experienced a vaccine-related injury

    • Stabilize the vaccine supply

    • Minimize the number of inappropriate claims

    • Coordinate immunization record-keeping

    • Require health care professionals to report certain adverse events via VAERS

    • Standardize vaccine warnings by creating Vaccine Information Statements

    • Decrease civil litigation

  • Successful – US presently has the highest immunization rates and the lowest rates of most vaccine-preventable disease in the nation’s history.

Cholera

  • While the oral cholera vaccine (OCV) is not routinely recommended in developed countries, it is generally available without prescription and is widely used for prevention of traveler’s diarrhea in those travelling to third world countries.

  • Unexpected potential benefit - retrospective observational studies show reductions in colorectal cancer (Ji J et al. Gastroenterology. 2017) , breast cancer (Br J Cancer. 2020. 124. 506-512), and prostate cancer (Ji J et al. Nat Commun. 2018).

Covid (SARS-CoV-2)

  • Types of vaccines (JAMA Insights. JAMA. 2021. 325. 1318-1320)

    • mRNA vaccines - “lipid nanoparticles are used to protect the prefusion-stabilized S protein-encoding mRNA en route to the intracellular space. The host uses the mRNA to make the target protein which induces a coordinated immune response.” The mRNA never enters the nucleus of the cell; the spike protein, synthesis of which is triggered by the vaccine, is displayed on the outside of the cells of the human body, and triggers an immune response against the SARS-CoV2 virus if the individual is exposed to the virus post vaccination.

      • Adverse events

        • Immediate (within 30 minutes) - very infrequent; anaphylaxis estimated at 1 incident of anaphylaxis per 2.5 million - 5 million doses administered

          • Anaphylactic reaction to PEG (which can be tested by an allergist, and is very rare) might be the cause of anaphylactic reactions to the mRNA vaccines

        • Delayed (hours to days after the injection) - common, including fever, sore arm, occasional rashes, virtually never severe

      • mRNA vaccines which are available in 2021

        • Pfizer - 2 shots 3 weeks apart; >90% efficacy

        • Moderna - 2 shots 4 weeks apart; > 90% efficacy

    • Viral Vector vaccines - “use replication-deficient viruses engineered to express the genetic sequence of the antigen of interest in host cells.” The DNA in the adenovirus is modified so that it produces a key part of the SARS-CoV2 virus particle, to which the body then develops an immune response. The adenovirus that delivers the DNA particle cannot multiply, so it does not cause infection. Effective at preventing hospitalization and death but varying efficacy in preventing clinical disease. Note that substantial exposure to the approximately 70 types of circulating human adenoviruses might dampen the immune response due to pre-existing exposure; viruses specifically chosen with a low seroprevalence in humans.

      • Johnson & Johnson (Jannsen) - human adenovirus; 1 dose.

        • Adverse events

          • Anaphylactic reactions are very rare, and might be caused by an anaphylactic reaction to polysorbate (which can be tested by an allergist)

          • Rare blood clots - cerebral venous sinus thrombosis - see just below

          • MI (heart attack) and PE (blood clot to lung) - see just below

        • Vaccine “paused” by CDC and FDA on April 14, 2021. As per an alert from NYS DOH, “As of April 12, 2021, approximately 6.85 million doses of the Johnson & Johnson (J&J) COVID-19 vaccine (Janssen) have been administered in the United States. The Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) are reviewing data involving six U.S. cases of a rare type of blood clot in individuals after receiving the J&J COVID-19 vaccine that were reported to the Vaccine Adverse Events Reporting System (VAERS). In these cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) was seen in combination with low levels of blood platelets (thrombocytopenia). All six cases occurred among women aged 18 48 years. The interval from vaccine receipt to symptom onset ranged from 6 13 days.“ Vaccine available again in the US in the week of April 26, 2021.

        • Case series data on 46.5 million adults in France who received a Covid vaccine. Published conclusion is “In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with an increased incidence of MI and PE.” (Ann Intern Med. 2022. 175. 1250-1257).

      • AstraZeneca - chimpanzee-derived adenovirus; 2 doses 4 - 12 weeks apart. Not yet approved in the US, effective May 23, 2021.

    • Inactivated and protein subunit vaccines

      • “Creation of inactivated vaccines derived from virus grown in culture and then chemically inactivated, which may deliver stably expressed, conformationally native antigenic epitopes.” Sinopharm and Sinovac vaccines in development.

      • “Delivery of the S protein as a recombinant protein subunit within one of several cell-based systems that support protein expression.” Novavax vaccine in development - 2 doses 21 days apart

    • UPDATED information, November 2021

      • Pfizer vaccine approved by the FDA for children ages 5-11, and CDC on November 2 recommends the vaccine for children ages 5-11.

      • Boosters of Pfizer, Moderna, and J&J approved by the FDA in late summer/fall of 2021, with guidance that it is acceptable (and might be more effective in some circumstances) to give a booster of a vaccine other than the vaccine used for the initial immunization. Boosters recommended for those over age 65, those under age 65 and with chronic medical conditions associated with an increased risk of severe Covid, and those who work in professions such that they are occupationally exposed to Covid in the care of those with Covid.

    • UPDATED information, October 2022

      • FDA and CDC in September 2022 approved bivalent vaccines effective against both the ancestral strain of Covid-19 and the BA.4 and BA.5 strains.

      • The bivalent vaccine should NOT be administered until after immunization with a monovalent vaccine (those approved in 2020/2021)

Diptheria

  • 175,885 annual cases prior to vaccine (MMWR. 1999. 48. 243), 21,053 annual cases 1936-1945, with 1822 annual deaths (JAMA. 2007. 298. 2155-2163); no cases in 2005 (MMWR. 2007. 54. 2); no cases in 2006 (MMWR. 2007. 56. 33).

  • Vaccine developed between 1906 and 1946; universal vaccination recommended in 1940’s, with DPT combination vaccine available in 1946.

  • Historically, ~10% mortality rate.

  • Toxin mediated disease caused by the bacterium Corynebacterium diptheriae; myocarditis and neuritis are the most common complications.

  • Universal vaccination recommended in 1940’s.

  • 85% community immunity required for ‘herd immunity.’

  • In 2006 in the US, only 85.2% of 19-35 month olds fully vaccinated with DTP (CDC data), compared with 94% in Canada and 98% in Mexico (WHO data).

  • Tetanus-diptheria (Td) toxoid recommended every 10 years for adults; but ‘compliance’ with this guideline is low, so the lack of cases in adults suggests that the childhood series is adequate for lifelong protection.

Hepatitis A 

  • 26,796 annual cases were reported annually to public health agencies prior to vaccination (MMWR. 1999. 48. 243), representing an estimated 270,000 infections per year when anicteric disease and asymptomatic infections are taken into account (Pediatrics. 2002. 109. 839-845).

  • 4488 cases in 2005 (MMWR. 2007. 54. 2); 3579 cases in 2006 (MMWR. 2007. 56. 33).

  • First vaccine introduced in 1995, recommended for universal use in 2006

  • In 2005, 5 vaccines are available worldwide; two inactivated vaccines are approved in the U.S.

  • Indications as per 12/96 recommendations as per CDC and ACIP (MMWR. 1996. 45. 1-30)

    • Persons traveling to or working in countries with high or intermediate endemicity of hepatitis A virus infection.

    • Men who have sex with men.

    • Illicit drug users.

    • All persons with hemophilia who receive replacement therapy.

    • Persons with occupational risk (i.e. researchers working with hepatitis A virus in laboratories).

    • Persons with chronic liver disease.

    • Prevaccination testing may be cost effective in adults greater than age 40 years old.

  • In 1999, ACIP expanded recommendations to include vaccination of children living in states that had consistently elevated hepatitis A rates (MMWR. 1999. 48. 1-37).

  • Two doses 6-18 months apart. Protective immunity is conferred 2-4 weeks after the first dose; the second dose ensures long-term protection.

Hepatitis B 

  • 5% lifetime risk for the general population.

  • HBV is 100 times more infectious than HIV virus.

  • Over 50% of people in the United States who acquire hepatitis B acquire it through sexual activity with an infected person.

  • 5% of patients go on to chronic infection; 1-2% develop fulminant hepatitis.

  • 21,102 annual cases prior to vaccine (MMWR. 1999. 48. 243); 5119cases in 2005 (MMWR. 2007. 54. 2); 4713 cases in 2006 (MMWR. 2007. 56. 33).

  • Vaccine, introduced in 1983, and recommended for universal use in 1991.

    • Engerix B (GSK) and Recombivax HB (Merck) - 3 doses at 0, 1, and 6 months

    • Heplisav-B (Dynavax) FDA approved in 2017 and requires only 2 doses at 0 and 1 month, licensed for use in adults > 18 years old. In clinical trials, this vaccine is more immunogenic, and causes more injection-site reactions. Rates of serious adverse events similar to the 3-dose vaccines. Long term safety not yet established in 2018 (JAMA. 2018. 319. 822-823).

  • Indications:

    • Heterosexual, gay, and bisexual men who have had more than one sexual partner during a six month period.

    • People who have a sexually transmitted disease or have ever had a sexually transmitted disease.

    • Sexual partners and household contacts of hepatitis B carriers.

    • Sexual partners of intravenous drug users.

    • CDC recommends giving this vaccine at birth - CONTROVERSIAL public policy.

    • ACIP (2022) recommends universal vaccination of adults aged 19-59, and adults older than age 59 with risk factors

  • Screen individuals who have emigrated from a high endemic area.

  • Pre-vaccination testing is only indicated if the estimated likelihood of infection is greater than 30%.

Herpes zoster – see ‘shingles’

HPV Vaccine for Prevention of cancer of the cervix (Gardasil and Cervarix)

  • HPV is the most common sexually transmitted disease in the US – each year 6.2 million Americans acquire a new genital HPV infection; most infections are asymptomatic.

  • CDC ACIP recommendations

    • 2006 - routine vaccination of females at age 11 or 12, with catch up vaccination through age 26.

    • 2011 - routine vaccination of males at age 11 or 12, with catch up vaccination through age 21.

    • NOTE in 2018 the FDA approved the 9-valent vaccine for use in ages 9 - 45 in women and men

  • Vaccine options – all are intramuscular

    • Gardasil - quadrivalent vaccine (protective against HPV types 6, 11, 16, and 18). Licensed in 2006.

    • Cervarix – bivalent vaccine (protective against HPV types 16 and 18). Licensed in 2009.

    • Gardasil 9 – effective against types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Licensed in 2014.

  • Vaccine dosing

    • Three doses for all age groups, historically

    • In October 2016 the CDC recommended a 2-dose schedule for adolescents who obtain the first vaccination before age 15.

  • HPV types 16 and 18 are estimated to cause 70% of cervical cancer, and the additional 5 types in the 9 valent vaccine cause an additional 15-20% of cervical cancers.

  • HPV types 6 and 11 cause 90% of genital warts.

  • Effectiveness

    • Approval based on data in 16 - 24 year old women that the vaccine reduces the incidence of atypical cervical cells named CIN2 and CIN3 (precancerous lesions).

      • Magnitude of benefit upon incidence of cervical cancer is unknown (progression of CIN3 to cervical cancer may be as low as 12%).

      • Data from a nationwide Swedish health registry indicates a 50% reduction in risk of invasive cervical cancer in association with vaccination between the ages of 10 - 30 (N Engl J Med. 2020. 383. 1340-1348).

    • Note that the vaccine is recommended at age 12, but the only data in girls at this age is immunologic data, not clinical data.

    • Cost effectiveness: “The current HPV vaccination program (to age 26 in females and to age 21 in males) is predicted to be cost saving. Extending vaccination to older ages (age 45) is predicted to produce small additional health benefits …” (Ann Intern Med. 2020. 172. 22-29).

    • Nationally representative data show increasing effectiveness based on herd impacts ((Ann Intern Med. 2022. 175. 918-926).

  • Safety - there is controversy regarding safety of this vaccine (Jorgensen L et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. 23. 165-168); The HPV Vaccine on Trial by Mary Holland JD, Kim Mack Rosenberg JD and Eileen Lorio. 2018).

    • Safety studied in clinical trials in over 29,000 males and 30,000 females prior to licensure of the vaccine in 2006.

    • As of May 31, 2010, 29.5 million doses of vaccine distributed in the U.S. and 16,140 VAERS, 8% of those considered serious, including 53 reports of death.

    • As per the CDC website (cited by Tori Hudson, ND in her column in October, 2010 Townsend Letter), all reports of serious adverse events have been carefully analyzed by medical experts, and no common pattern identified. Thus, uncertain how many of the 16,140 serious adverse events actually caused by the vaccine as opposed to independent events temporally associated with vaccination.

    • In an article in the February/March 2014 Townsend Letter, Gary Null and Nancy Ashley state “compared with the mandated vaccines which are given with greater frequency, Gardasil still has the most adverse events reported to the … VAERS of any vaccine.”

    • A concern is that an unintended consequence of vaccination might be an increase in precancerous cervical lesions caused by serotypes other than the four serotypes in the quadrivalent vaccine (Haug, CJ. Editorial. N Engl J Med. 2008. 359. 861-862).

    • Manufacturer (Merck) data shows that vaccination of females with current or past HPV 16 or 18 infection were 44.6% more likely to develop CIN2 or CIN3 lesions.

    • VAERS data suggests that Gardasil might be dangerous to administer in pregnancy – 1300 adverse reactions reported in the first 5 years after approval.

Influenza 

  • Scope:

    • In the US, variability in incidence from year to year, but generally with millions of annual cases, hundreds of thousands of annual hospitalizations and tens of thousands of estimated deaths.

    • 90% deaths occur in people over age 65.

    • Vaccination rates rarely exceed 50% in children and young adults, and rarely exceed 70% in adults over age 65 (MMWR. 2022. 71. 1366-1373).

  • Cost:

    • $8/shot under Medicare in 1995.

  • Cost effectiveness:

    • A controlled 4-year, 10-state demonstration trial conducted by CDC and HCFA demonstrated that even if the vaccination rate is only 40%, there is a 40% reduction in hospitalizations for influenza and 20% reduction in the death rate from influenza, with a cost saving of $145 per year of life gained (MMWR. 1993. 42. 601-604).

  • Efficacy:

    • Randomized double-blind placebo controlled trial. Netherlands, 1838 subjects, age >60 (JAMA. 1994. 272. 1661-1665).

      • Incidence of serologic influenza: 4% with vaccine and 9% in controls.

      • Incidence of clinical influenza: 2% with vaccine and 3% in controls.

    • Data derived from health care databases, in which information about immunization is related to outcomes such as hospitalization and death, consistently shows that influenza vaccination in the elderly is associated with substantial reductions in the risk of wintertime pneumonia-related and influenza-related hospitalizations and deaths (Editorial. N Engl J Med. 2007. 357. 1439-1441). Vaccination is also associated with reductions in deaths from any cause (JAMA. 1993. 270. 1956-1961), and with reductions in rates of heart attacks and strokes (N Engl J Med. 2003. 348. 1322-1332).

      • Confounding could explain these data (i.e. healthier individuals are the ones predominantly vaccinated).

      • Many of the cohort studies were limited in to a single site or one or two seasons of analysis, and thus the outcomes could be a function of the significant seasonal and regional variation in morbidity, a phenomenon known to occur (Am J Epidemiol. 2006. 163. 316-326).

    • The overall increase in wintertime deaths and hospitalizations as immunization rates increased between 1986 – 1996 raise the possibility that vaccination does not reduce the rate of hospitalization in the elderly (Arch Intern Med. 2005. 165. 265-272).

    • A cyclical regression model in which data from 1968-2001 was stratified by 5-year age group found that the decline in influenza mortality after the 1968 pandemic was associated with the acquisition of immunity to influenza A (H3N2) virus. In this model, there was NOT a correlation between vaccination with influenza vaccine and decreased mortality! The authors conclude that observational data substantially overestimates vaccination benefit (JAMA. 2005. 165. 265-272).

    • A systematic review of 5 RCTs, 49 cohort studies, and 10 case-control studies concluded that influenza vaccination in older patients was associated with a 23% relative reduction in influenza-like illness and no reduction in confirmed influenza. Among nursing home patients the vaccine reduced death from pneumonia or influenza by 42%. In 2 RCTs with 2047 patients, vaccination had an overall effectiveness of 43% for preventing influenza-like illness, and in 3 RCTs with 2217 patients; vaccination had an effectiveness of 58% for preventing influenza (Lancet. 2005. 366. 1165-1174).

    • Cohort data gathered during 10 seasons in 3 geographically different HMOs showed that “influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community dwelling elderly persons” (N Engl J Med. 2007. 357. 1373-1381). This data incorporated 713,872 person years of observation; average immunization rates were 58%. It is known that confounding by functional status, in which the frail are less likely to receive vaccination (Int J Epidemiol. 2006. 35. 345-352) can confound data collection of this type; a lack of difference in the rates of summertime hospitalization between vacinees and those not vaccinated suggests that this confounding factor does NOT explain the positive results attributed to influenza vaccination (Editorial. N Engl J Med. 2007. 357. 1439-1441).

    • However, although flu vaccination rates in the U.S. have increased from 15% to 65% since 1980, mortality studies cannot confirm any decrease in flu-related deaths, according to researchers at George Washington University (Lancet Infect Dis. 2007. 7. 656-666).

    • Effectiveness in community-dwelling elderly – vaccination is associated with a reduction in the composite endpoint of hospitalizations for influenza and pneumonia, combined with all-cause mortality, but vaccination is not associated with a statistically significant reduction of all-cause mortality alone. (Arch Intern Med. 2012. 172. 484-491). A accompanying invited commentary (492-493) states that the results of this study are consistent with results of several prior studies, and indicates that high-dose vaccine or adjuvant vaccine may represent a superior strategy of vaccination for the elderly.

    • Effectiveness in patients on hemodialysis – data suggests that influenza vaccine has a minimal effect on morbidity and mortality in patients with ESRD. The authors conclude that alternate strategies, such as high-dose vaccine, adjuvant vaccine, or multiple doses of vaccine should be considered (Arch Intern Med. 2012. 172. 548-554).

    • Effective at reducing influenza-like illness and influenza in healthy adults, with good safety profile, but a NNT of 37-71 to prevent one case of influenza, as per a Cochrane review of 90 studies, including 69 RCTs (Cochrane Database Syst Rev. 2014. CD001269).

  • Benefits above and beyond protection from influenza

    • Lower risk of major cardiovascular events, based on a meta-analysis of 5 published and 1 unpublished RCT (n=6737). Greatest treatment effect seen amongst highest risk patients (JAMA. 2013. 310. 1711-1720).

    • In a RCT of 2571 patients with a history of MI or with high-risk CAD, influenza vaccine reduced the risk of CV outcomes, including mortality at 12 months. The NNT to prevent on death was 51, and this magnitude of benefit is similar to the magnitude of benefit seen with treatment post MI with ACE inhibitors, ARB agents, and statins (Circulation. 2021. 144. 1476-1484).

    • Lower risk of Alzheimer’s - in those over age 65, data in 1.8 million people shows a 40% lower rate of Alzheimer’s over the next four years in those who received a flu vaccine (J Alzh Dis. 8/2/22 - cited in Consumer Reports on Health)

  • Safety:

    • Immediate hypersensitivity reaction occurs in 1 in 4 million recipients.

    • Local soreness occurs in 25-60% of recipients. This is the only side effect more common than in the placebo group in a RCT (JAMA. 1990. 265. 1139-1141).

    • Mild constitutional symptoms (fever, myalgias, arthralgias) which occur in 4-7% of recipients are no more common than in a placebo group.

    • Systemic febrile reactions were more common in 1960's with less purified vaccines.

    • Subdeltoid bursitis - incidence estimated at 8 cases per 1 million vaccinations (Ann Intern Med. 2020. 173. 253-261 and editorial 308). Technique (aim for the midpoint of the deltoid muscle, 2-3 finger breaths below the acromion process; use a 5/8 inch needle for those < 60 kg, 1 inch needle for those 60-70 kg, 1 - 1.5 inch needle for women 70 - 90 kg and men 70 - 118 kg, and a 1.5 inch needle for women > 90 kg and men > 118 kg) likely reduces the risk.

    • No evidence that the flu vaccine causes respiratory symptoms.

    • Safety when administered to pregnant women

      • In a Danish study of offspring of women vaccinated with H1N1 influenza vaccine in 2009, there was no increased risk of hospitalization or any of 23 diseases in children who were followed to age 5 (JAMA Pediatr. 2017. 171. 239-248).

      • In a retrospective cohort study of 100,000 Canadian children followed from birth to age 5 years, born to mothers who received H1N1 influenza vaccine in 2009, with multiple health outcomes examined, there were no differences in health outcomes as compared with children of unvaccinated mothers (BMJ. 2019. 366. 14151).

      • In a cohort study in Sweden of 39,726 infants who were prenatally exposed to influenza vaccine (i.e. mother immunized during pregnancy), at a mean follow up of 6.7 years, there was no association between maternal H1N1 influenza vaccination during pregnancy and risk for autism-spectrum disorder in the offspring (Ann Intern Med. 2020. 173. 597-604 and editorial 658-659).

  • Indications

    • In 2010, the US adopted a policy of recommending vaccination for all persons age 6 months or older (initially recommended in 1960, and over the years the ages/medical conditions for which it was indicated gradually expanded).

    • Prior to 2010, vaccination was recommended for

      • All persons age 50 and older.

      • All children age 6-59 months old.

      • All children age 6 months through 18 years receiving chronic aspirin therapy (and thus at risk for Reye’s syndrome post influenza).

      • All persons with any of the following conditions: chronic disorder of the pulmonary or cardiovascular system, chronic metabolic disease (including diabetes), renal dysfunction, hemoglobinopathy, immunosuppression (due to HIV or medications).

      • Women who will be pregnant during the influenza season.

      • Residents of nursing homes and chronic care facilities.

      • All persons who have contact with high risk individuals (including health care professionals).

      • Household contacts or caretakers of children up to 59 months of age or adults over age 50.

  • Types of influenza vaccines

    • Trivalent or quadrivalent inactivated vaccines, administered intramuscularly

    • Live attenuated vaccine, administered via nasal spray – indicated only in immunocompetent individuals ages 2-49.

    • High-dose vaccines for seniors (those over age 65) - three brand name vaccines available in 2022

      • Fluzone High-Dose Quadrivalent with four times the antigen in an ordinary flu vaccine

      • Flublok Quadrivalent with three times the antigen in an ordinary flu vaccine

      • Fluad Quadrivalent with an adjuvant that stimulates a stronger immune response

Measles 

  • Prevalence and mortality

    • WHO reports (WHO website) that prior to introduction of the vaccine in 1963, major epidemics occurred every 2-3 years, causing an estimated 2.6 million deaths per year internationally.

    • 503,282 annual US cases prior to vaccine (MMWR. 1999. 48. 243); 530,217 annual cases 1953-1962 with 440 annual deaths (JAMA. 2007. 298. 2155-2163).

    • 66 cases in 2005 (MMWR. 2007. 54. 2); 58 cases in 2006 (MMWR. 2007. 56. 33)

    • 592 cases from January 1 – August 29 2014 (Perspective. Oct 30, 2014 N Engl J Med).

    • 649 cases between 9/18/18 - 7/15/19, in an outbreak in New York City. Pneumonia occurred in 37 patients, hospitalization in 49 patients and intensive care treatment was required in 20 patients. Cost of outbreak estimated at $8.4 million (N Engl J Med. 2020. 382. 1009-1017).

  • Vaccination rates and cases of measles in the UK (WHO data)

    • Measles vaccination rates were 92% in 1996, and dropped to a nadir of 80% in 2003, based on concern about the vaccine and autism. The vaccination rate in 2006 was back up to 84.4%.

    • There were 100 or less cases of measles reported in the UK in 1998-2002; there were over 700 cases in 2006!

    • Since MMR is usually given as one vaccine, there was also a marked increase in cases of mumps in the UK (in 2005), with over 60,000 cases reported, compared with fewer than 1000 cases in 2000 - 2004.Highly contagious – reproduction rates estimated at 12-18.

  • Symptoms include cough, coryza, conjunctivitis, high fever, maculopapular rash.

  • Complications include otitis media, diarrhea, dehydration, pneumonia, encephalitis, and death.

  • Case fatality rate in US is 0.2 – 0.3%; in developing world it is 2 - 15 %.

  • Universal vaccination recommended in 1963.

  • 92% - 94% community immunity required for ‘herd immunity.’

  • Measles vaccine is effective (i.e. induces immunity to measles) in only 95% of those administered the vaccine; thus 99% community immunization is required to establish ‘herd immunity.’

  • In 2006 in the US, only 92.4% of those aged19-35 month were fully vaccinated with measles vaccine (CDC data), compared with 94% in Canada and 96% in Mexico (WHO data).

  • SAFETY - published data shows no association between MMR vaccine and autism

    • There are anecdotes of parents who observe regressive autism in their child soon after MMR vaccine - this observation does not prove cause and effect.

    • In 1998 Andrew Wakefield et. al. reported on 12 children with developmental delay, 8 of whom were diagnosed with autism within 4 weeks of receiving MMR vaccine (Lancet. 1998. 351. 637-641).

      • This study received wide publicity and likely was a key factor in a significant decrease in vaccination rates in the UK and other countries.

      • This study was retracted in 2010 (Lancet. 2010. 375. 445).

    • A retrospective analysis of 537,303 children born in Denmark between 1991 and 1998 (2,129,864 person years) showed no association between MMR vaccination and autism, and also no association between the child’s age at the time of vaccination or the time since vaccination and the diagnosis of autism (N Engl J Med. 2002. 347. 1477-1482).

    • The Institute of Medicine Vaccine Safety Committee reported in 2004 that “the data favors rejection of an association” between MMR vaccination and autism

    • A meta-analysis of 5 large cohorts in the US (n = 1,256,407 children) and also 5 case-control studies (n = 9920 children) in the US found no relationship between MMR vaccination and autism (JAMA. 2015. 313. 1534-1540).

    • A retrospective analysis of 657,461 children born in Denmark between 1999 and 2010 (5,025,754 person years) showed no association between MMR vaccination and autism. Furthermore, analysis of 6517 children in the cohort with autism did not show a clustering of cases of autism post MMR vaccination and did not show an increased rate of autism in susceptible children post MMR vaccination (Ann Intern Med. 2019. 170. 513-520 and editorial 567-568).

  • BENEFIT - nonspecific effects of measles vaccine

    • There is data in developing countries that measles vaccination is associated with a reduction in rates of all other infections by 1/3, with significantly lower rates of pneumonia, sepsis and death (Ugeskr Laeger. 1996. 158. 5944-5948; Int J Epidemiol. 2003. 32. 106-116).

    • Proposed explanations for this nonspecific benefit or reduction in prevalence and mortality from all infectious disease (Schor, Jacob. Townsend Letter. November 2021. 80-83).

      • There is data that measles infection damages the immune system, causing immunosuppression that may last as long as 30 months (Mina MJ et al. Sciences. 2019. 266. 6465; Petrova VN et al. Sci Immunol. 2019. 4[41]. pii:eaay6125).

      • The measles vaccine itself may act as an immune stimulant.

      • Adjuvants such as aluminum in the vaccine may broadly stimulate an enhanced immune system TH2 response and B cell activation.

  • Every adult born after 1956 should have two separate vaccinations, at least 30 days apart, with both administered after the first birthday.

  • The second dose was recommended in 1989 to improve measles control.

  • There is no evidence of adverse effects if MMR vaccine is given to those already immune to one or more components.

Meningococcal vaccine

  • Meningococcal meningitis and meningococcemia are uncommon, but case fatality rate for meningococcal disease is 9-12%, and for meningococcemia is as high as 40%. Up to 20% of survivors of meningococcal disease have permanent sequale.

  • As many as 10% of adults are asymptomatic and transient carriers of Neisseria meningitides, the bacteria responsible for meningococcal disease.

  • Almost all invasive disease is caused by 5 serogroups.

  • There are two tetravalent vaccines – vaccination is recommended for college freshman living in dormitories, during outbreaks, and in persons at increased risk of meningococcal disease (i.e. military recruits).

Mumps

  • 152,209 annual cases prior to vaccine (MMWR. 1999. 48. 243); 162,344 annual cases 1963-1968 with 39 annual deaths (JAMA. 2007. 298. 2155-2163); 314 cases in 2005 (MMWR. 2007. 54. 2); 6584 cases in 2006 (MMWR. 2007. 56. 33).

  • Universal vaccination recommended in 1968.

  • 86% community immunity required for ‘herd immunity.’

  • In the UK, immunization with MMR decreased to 80% in 2003, and there was an outbreak of mumps in 2005, with over 60,000 cases reported, compared with fewer than 1000 cases in 2000-2004 (WHO data).

Pertussis

  • 147,271 annual cases prior to vaccine (MMWR. 1999. 48. 243); 200,752 annual cases 1934-1943 with 4034 annual deaths (JAMA. 2007. 298. 2155-2163); 26,616 cases in 2005 (MMWR. 2007. 54. 2); 15,632 cases in 2006 (MMWR. 2007. 56. 33).

  • Vaccine developed between 1906 and 1946; universal vaccination recommended in 1940’s, with DPT combination vaccine available in 1946.

  • Only 1010 cases in 1976 (historic low).

  • Highly contagious respiratory disease caused by the bacterium Bordetella pertussis.

  • Universal vaccination recommended in 1940’s.

  • 94% community immunity required for ‘herd immunity.’

  • In 2006 in the US, only 85.2% of 19-35 month olds fully vaccinated with DTP (CDC data), compared with 94% in Canada and 98% in Mexico (WHO data).

  • Due to the resurgence of pertussis, and a new acellular pertussis vaccine which is safe in adults, booster with tetanus, diphtheria, and pertussis is now recommended for some adults.

    • Tdap is recommended for all adults through age 64 as a one-time dose (in place of one of the q10 year Td toxoid boosters recommended). Adacel (sanofi Pasteur) and Boostrix(GlaxoSmithKline) are the brand name products licensed for use in teens and adults.

    • DTaP (the capital letters denote more antigen) is recommended for infants and small children.

Pneumonia - pneumococcal polysaccharide vaccine (PPSV – brand name Pneumovax)

  • Scope:

    • 40,000 deaths/year from pneumococcal disease.

    • 6000 deaths/year from invasive disease.

    • 500,000 cases of pneumococcal pneumonia/year; 175,000 annual hospitalizations.

    • 3000 - 6000 cases of pneumococcal meningitis/year.

    • Bacteremia occurs 25-30% of the time in patients with pneumococcal pneumonia.

    • Mortality is 25-30% with pneumococcal bacteremia (approximately 60% in the elderly).

    • Resistant strains will make medical treatment more difficult.

  • History:

    • Approved based on studies in young African gold miners in the 1940’s - efficacy 90%.

    • No large prospective randomized studies ever done.

    • 1977 - 14 valent vaccine - covers 68-80% of bloodstream isolates.

    • 1983 - 23 valent vaccine - covers 85-90% of bloodstream isolates, even though there are 84 recognized serotypes (in 1995).

  • Indications:

    • All individuals over age 65.

    • Individuals over age 2 with alcoholism, cirrhosis, cerebrospinal fluid leaks, congestive heart failure, coronary artery disease, diabetes, emphysema, lupus, renal failure, nephroticsyndrome, lymphoma, multiple myeloma, functional or anatomic asplenia, organ transplant, and AIDS.

    • Individuals living in special environments (some Native Americans).

    • ACIP recommends revaccination at 6 years for those people with asplenia, renal failure, nephrotic syndrome, and transplant, based on data that antibody levels wane 5 years after vaccination.

    • ACIP recommends revaccination at age 65 for those immunized before age 65.

    • USPSTF II in 1996 recommended universal re-immunization at age 75.

  • Cost:

    • $20 - $25 in 1995.

  • Cost effectiveness:

    • A cost-effectiveness analysis concluded that pneumococcal vaccine to prevent bacteremia in individuals over age 65 is cost saving (JAMA. 1997. 278. 1333-1339).

    • Incidence of invasive pneumococcal disease in African Americans, Native Americans, and Alaska Natives is 2-10 times higher than in Caucasians, and is manifest at an earlier age, suggesting that immunization at an earlier age may be advisable.

    • A cost-effectiveness analysis suggests that routine immunization for individuals at age 50 costs $2477/QALY for African Americans and $8195/QALY for Caucasians, with cost savings for individuals age 50 and at high risk for pneumococcal disease. This analysis uses available data on vaccine protection against invasive pneumococcal disease (bacteremia and meningitis) and assumes a six year duration of benefit of vaccination (Ann Intern Med. 2003. 138. 960-968 and 999-1000).

  • Safety:

    • <1% systemic reactions (anaphylaxis in 5 recipients per million).

    • 50% experience mild erythema and pain at site of injection.

    • Revaccination within 13 months may cause more severe local reactions.

  • Efficacy against pneumonia in those with COPD - beneficial in a Cochrane review of 9 RCTs (Cochrane Database Syst Rev. 2017. 1. CD001390).

  • Efficacy against invasive (blood/cerebrospinal fluid) disease: In general, observational studies have found vaccination beneficial, but clinical trials have been inconclusive (Review article. Cleve Clinic J Med. 2007. 74. 401-414).

    • Case control study with 1054 patients (N Engl J Med. 1991. 325. 1453-1460).

      • Patients received either 14 or 23 valent vaccine - 983 of the 1054 case patients were infected with serotypes in the vaccine.

        • Aggregate efficacy of 56% against serotypes in vaccine.

        • 61% efficacy in 808 immunocompetent (congestive heart failure, emphysema, renal failure, diabetes, alcohol abuse).

        • 21% efficacy in 175 immunocompromised (asplenia, transplants, nephrotic syndrome, lupus, hematologic malignancy).

        • 93% efficacy in those under age 55; 40% efficacy in those over age 85.

      • Efficacy declined over time - not sure whether due to decreased immunity or to exposure to serotypes not in vaccine.

      • No evidence that revaccination improves long-term efficacy.

      • Note: 3 of 4 published case-control studies show benefit; only the smallest does not show benefit.

    • Indirect cohort analysis. 1978-1992. 2837 patients (JAMA. 1993 .270. 1826-1831).

      • Overall efficacy - 57%.

      • Diabetes - 84% efficacy.

      • Coronary artery disease - 73% efficacy.

      • Congestive heart failure - 69% efficacy.

      • Emphysema - 65% efficacy.

      • Anatomic asplenia - 77% efficacy.

      • Immunocompetent over age 65 - 75% efficacy.

      • Sample size too small to evaluate efficacy for cirrhosis, renal failure, sickle cell anemia, and hematologic cancers.

      • Efficacy in AIDS not analyzed in this study.

      • Efficacy did not decline over a period of 9 years.

    • Randomized double-blind, placebo-controlled trial of 2300 veterans. No efficacy documented, but based on incidence of serious infection of only 2-3/1000 even in high risk groups, a study would require 20,000 participants to determine conclusively that a vaccine is 50- 60% effective.

    • Data in a population based cohort of 3415 patients hospitalized with community acquired pneumonia showed that those with prior vaccination had about a 40% lower rate of mortality or admission to the ICU, providing indirect evidence of efficacy (Arch Intern Med. 2007. 167. 1938-1943).

    • No studies have examined vaccine efficacy after a second dose of vaccine.

  • Additional considerations (Arch Intern Med. 1994. 154. 373 and Arch Intern Med. 1994. 154. 2531):

    • Definitive diagnosis of pneumococcal pneumonia is difficult because oropharyngeal flora can contaminate sputum.

    • Serotypes which cause pneumococcal bronchitis (one end point in the randomized study) are different from serotypes which cause pneumonia.

    • One can only can assume that the vaccine is also 50-60% effective against pneumonia (this is an extrapolation of data which shows 50-60% efficacy against invasive pneumococcal disease).

    • Even though there is no large, prospective, controlled study of vaccine efficacy, the similar percentages reported for efficacy in case-control studies and indirect cohort analysis supports a conclusion that the vaccine is effective.

    • Pneumonia is due to aspiration - pneumococcus causes only 5-25% of pneumonias - we have no data regarding whether a decreased incidence of pneumococcal pneumonia leads to an increased incidence of other pneumonias and/or an increased death rate from other pneumonias.

    • Even though the 23 valent vaccine covers only 68-75% of sputum isolates of pneumococcus, an additional 13% are likely to be covered by cross-reactivity.

  • New data (Ann Intern Med. 2003. 138. 960-968 and editorial 999-1000; Review article. Cleve Clinic J Med. 2007. 74. 401-414):

    • Cigarette smoking has been identified as a strong independent risk factor for invasive pneumococcal disease.

    • Serologic studies indicate that immune responses are lower after revacciantion.

    • Approximately half of individuals age 50-64 are candidates for pneumococcal vaccine.

    • Serotype replacement (emergence of serotypes not covered by the current vaccine) is a worrisome trend.

Pneumonia – pneumococcal conjugate vaccine (PCV - brand name Prevnar)

  • Recommended in 2015 by ACIP for all adults age 65 and older (in addition to Pneumovax). This is a new recommendation for a vaccine recommended for years for children – decision to expand coverage to all seniors based upon results of CAPiTA study, presented to ACIP at its June 2014 meeting (Ann Intern Med. 2015. 162. 214-223 and editorial 235-236). Booster - a booster is suggested every 5 years, as per Patient Centered Medical Home literature in 2024.

  • CAPiTA study – RCT of 84,496 adults age 65 years or older, which showed that the 13-valent pneumococcal conjugate vaccine was effective in preventing vaccine-type pneumococcal pneumonia and vaccine-type invasive pneumococcal disease (N Engl J Med. 2015. 372. 1114-1125).

  • Efficacy against pneumonia in those with COPD - beneficial in a Cochrane review of 3 RCTs (Cochrane Database Syst Rev. 2017. 1. CD001390).

  • Prevnar and Pneumovax induce immunity via different mechanisms – ACIP guidance regarding timing of immunization is as follows

    • For pneumococcal-naïve adults aged 65 years or older, administer Prevnar first, wait 6-12 months, and then administer Pneumovax.

    • For seniors for whom Pneumovax was already administered, wait at least one year before giving Prevnar

    • For those who meet the criteria for Pneumovax booster vaccination, wait at least 5 years after the last dose of Pneumovax and 6-12 months after the dose of Prevnar.

  • Prevnar 13 was the version in 2015; Prevnar 21 is the version in 2024.

  • CMS updated coverage on 2/2/15 such that Medicare will cover the cost of both vaccines as long as they are administered at least 1 year apart.

Polio

  • 16,316 annual cases prior to vaccine (MMWR. 1999. 48. 243); 19,794 annual cases acute poliomyelitis 941-1950 with 1393 deaths; 16,316 annual cases of paralytic poliomyelitis 1951-1954 with 1879 annual deaths (JAMA. 2007. 298. 2155-2163); 1 case in 2005 [imported, vaccine associated] (MMWR. 2007. 54. 2); 0 cases in 2006 (MMWR. 2007. 56. 33).

  • Universal vaccination recommended in 1955, coinciding with licensure of inactivated poliovirus vaccine.

  • 50-93% community immunity required for ‘herd immunity’ following OPV, with data for herd immunity with IPV not established.

  • In 2006 in the US, only 92.9% of 19-35 month olds fully vaccinated with DTP (CDC data), compared with 94% in Canada and 98% in Mexico (WHO data).

  • Polio vaccine and SV40 virus and cancer – the following is copied and pasted from the web site of the National Network for Immunization Information, http://www.immunizationinfo.org/iom_reports_detail.cfv?id=49, last updated 1/24/05. “Some of the polio vaccine administered from 1955-1963 was unknowingly contaminated with a virus, called simian virus 40 (SV40). The virus came from the monkey kidney cell cultures used to produce the vaccine. Because SV40 was not discovered until 1960, no one was aware that polio vaccine made in the 1950s could be contaminated. It is estimated that over 98 million Americans received one or more doses of polio vaccine during the period of 1955-1963. Most, but not all, of the contamination was in the inactivated polio vaccine (IPV). Once the contamination was recognized, steps were taken to eliminate it from future vaccines. No vaccines licensed for use in the US currently are contaminated with SV 40. Although SV40 has biological properties consistent with a cancer-causing virus, it has not been conclusively established whether it has caused cancer in humans. Epidemiological studies of groups of people who received polio vaccine during 1955-1963 do not show an increased cancer risk. However, a number of studies have found SV40 in certain forms of cancer in humans, such as mesotheliomas—rare tumors located in the lungs—brain, and bone tumors; the virus has also been found to be associated with some types of non-Hodgkin's lymphoma. In 2002, the IOM’s Immunization Safety Review Committee considered that the available data was inadequate to conclude whether or not the contaminated polio vaccine may have caused cancer.”

  • Polio vaccine and AIDS – it has been hypothesized that field trials of an early oral poliovirus vaccine were the origin of the global AIDS epidemic. This theory received press based upon a widely publicized book, The River: A Journal to the Source of HIV and AIDS (1999) by British journalist Edward Hooper. There is now significant scientific evidence to support rejection of this theory. The evidence is summarized on the web site of the National Network for Immunization Information, http://www.immunizationinfo.org/immunization_science_detail.cfv?id=45, and in a scientific publication by Worobey et al (Nature. 2004; 428: 820).

Respiratory Syncytial Virus (RSV) [Commentary. ACP Journal Club. 2023. 176. JC62-JC63; ACP Internist newspaper. October 2023; Ideas and Opinions. Ann Intern Med. 2023. 176. 1419-1421; Editorials. N Engl J Med. 2023. 389. 2288-2289 and 2480-2481]

  • Virus identified in 1956; leading cause of acute respiratory illness worldwide. By 2 years of age, most children have been infected with RSV, with a wide range of severity of symptoms/outcomes.

  • Worldwide, in 2019 an estimated 33 million cases, 3.6 million hospitalizations, 101,400 deaths, and 26,300 in-hospital deaths among children under 5 years of age. 95% of acute lower respiratory infections and RSV-attributable deaths occurred in low- and middle-income countries (Lancet. 2022. 399. 2047-2064).

  • RSV causes as many as 160,000 hospitalizations and 10,000 deaths annually among adults ages 65 and older (Morbidity and Mortality Weekly Report (MMWR).  July 21, 2023. Those who are frail, those at advanced age (>75 years), those living in long term care facilities or in shelters, and those with medical comorbidities are at highest risk for hospitalization.

  • History of vaccination - setback in the 1960’s when a formalin-inactivated RSV vaccine was shown in clinical trials of seronegative children to be associated with fatal adverse events after natural infection with RSV during the following RSV season (Am J Epidemiol. 1969. 89. 422-434).

  • The Advisory Committee on Immunization Practices (ACIP) of the CDC recommended in June, 2023 that adults ages 60 years and older may receive a single dose of an RSV vaccine (two vaccines are FDA-approved at this time). Shared decision-making is recommended by the ACIP for those 60-65 years of age, with the ACIP members divided as to whether to recommend vaccination of all individuals over age 65 versus shared decision making.

  • In an ongoing RCT of 25,040 participants > age 60 in 17 countries, a single dose of an ASO1E adjuvanted RSVPreF3 OA vaccine had 83% efficacy against RSV-related lower respiratory tract disease over two RSV seasons (N Engl J Med. 2023. 388. 595-608). This vaccine is marketed by GSK as Arexvy.

  • In a RCT of 36,862 participants > age 60 in 40 centers in the US, a single dose of unadjuvanted Ad26.RSV.preF-RSV preF protein vaccine had 84% efficacy against RSV-related lower respiratory tract disease over two RSV seasons (N Engl J Med. 2023. 388. 609-620). This vaccine is marketed by Pfizer as Abrysvo.

  • NOTE these trials were underpowered to estimate vaccine efficacy against hospitalization or death.

  • NOTE no booster effect was seen in the trial of the GSK vaccine, in which a second dose was administered at 12 months.

  • NOTE that in these two trials, there were few participants older than age 75, and statistical significant benefit was NOT demonstrated in those older than 75.

  • Trials of both vaccines did report rare neuroinflammatory events (including Guillain-Barre) in vaccine recipients, but not in controls.

  • Limitations of the two trials (cited above) published in 2023 - under-enrollment of those at highest risk of hospitalization or death (i.e. frail, advanced age, comorbidities) and the duration of effectiveness of a single vaccine is unclear.

  • Cost (list price of vaccine) in 2023: $280 per dose of the GSK vaccine; $295 per dose of the Pfizer vaccine. In 2023, for those enrolled in Medicare, cost is covered by Medicare Part D (other vaccines such as influenza, pneumonia and Covid-19 are covered under Medicare Part B).

  • In 2023, based on limited data, advised to administer RSV vaccine alone, not simultaneously with other vaccines such as influenza, pneumonia or Covid-19.

Rotavirus (Editorial. N Engl J Med. 2014. 370. 568-569).

  • First vaccine. RotaShield (Wyeth Lederle) withdrawn from the market in 1999, less than 1 year after recommended for routine vaccination, due to occasional cases of intussusception (N EnglJ Med. 2001. 344. 564-572).

  • RotaTeq (Merck), a pentavalent vaccine (RV5) shown safe and effective in a trial of more than 60,000 infants (N Engl J Med. 2006. 354. 23-33).

  • Rotarix (GlasoSmithKline), a monovalent vaccine (RV1) shown safe and effective in a trial of more than 60,000 infants (N Engl J Med. 2006. 354. 11-22).

  • Recommended by WHO for immunization of children worldwide.

  • In the US, hospitalizations and emergency room visits have decreased 80% among immunized children (Pediatr Infect Dis J. 2011. 30. S30-S34; Clin Infect. Dis. 2013. 57. 13-20). Thus, in the US cohort of 4.5 million babies born each year, vaccination is estimated to prevent approximately 53,000 hospitalizations and 170,000 emergency room visits (CDC website).

  • In Mexico, deaths from diarrhea decreased 40% after implementation of a vaccination program (N Engl J Med. 2010. 362. 299-305).

  • In 2011, surveillance data in Mexico and Brazil showed a small but significant increase in the risk of intussusception 1-7 days after the administration of the first dose of vaccine (Clin Infect. Dis. 2013. 57. 1427-1434; N Engl J Med. 2011. 364. 2283-2292). Subsequent surveillance data in Australia showed the same (Clin Infect. Dis. 2013. 57. 1427-1434).

  • In 2013, the PRISM study in the US showed approximately 1.5 excess cases of intussusception within 21 days after the administration of the first dose of RV5 vaccine, on the basis of 8 cases among approximately 500,000 recipients of the vaccine. This study was not powered to detect a risk of intussusception after vaccination with RV1; it showed a total 3 cases within 7 days within 7 days after the first or second dose of RV1 among approximately 103,000 doses administered, which was not statistically significant (N Engl J Med. 2014. 370. 503-512).

  • In 2013, the VSD study showed 4 cases of intussusception within 7 days of the first dose of RV5 among 493,000 recipients of the vaccine, which was not statistically significant; it showed 6 cases of intussusception within 7 days after the first or second dose of RV1 among approximately 200,000 doses, which was statistically significant (N Engl J Med. 2014. 370. 513-519).

  • Interestingly, analysis of US data from 2001 - 2017 shows that rotavirus vaccination is associated with a lower risk of development of type I diabetes (Rogers MAM et al. Sci Rep. 2019. 13. 7727).

Rubella (German measles)

  • 47,745 annual cases prior to vaccine (MMWR. 1999. 48. 243); 47,745 annual cases 1966-1968 with 17 annual deaths (JAMA. 2007. 298. 2155-2163); 11 cases in 2005 (MMWR. 2007. 54. 2); 11 cases in 2006 (MMWR. 2007. 56. 33).

  • 823 cases of congenital rubella prior to vaccine (MMWR. 1999. 48. 243); 1 case in 2005 (MMWR. 2007. 54. 2); 1 case in 2006 (MMWR. 2007. 56. 33).

  • Universal vaccination recommended in 1969.

  • 83 - 85% community immunity required for ‘herd immunity.’

Shingles (herpes zoster) vaccine

  • Prior to vaccination, an estimated 1 million cases per year, with up to 1/3 developing postherpetic neuralgia. In 18% of individuals with shingles, postherpetic neuralgia can persist for months to years. As many as 50% of people who live to age 65 will have shingles at some point in their life (Mayo Clin Proc. 2007. 82. 1341-1349).

  • There is not a need to test serologically for previous exposure to chickenpox, as serologic surveys indicate nearly everybody born in the US prior to 1980 has had exposure to the chicken pox virus.

  • The vaccine is recommended for those with a previous bout of shingles, once the acute phase is resolved. Rates of herpes zoster recurrence appear to be similar to rates of first occurrence in immunocompetent individuals, based on a Mayo Clinic record review of 1669 persons with a medically documented episode of herpes zoster, providing data to support the recommendation to immunize those with a prior bout of shingles (Mayo Clin Proc. 2011. 86. 88-93).

  • Zostavax - live, attenuated vaccine

    • Approved 5/06 for healthy adults older than age 60 who are seropositive for varicella.

    • Recommended since 2008 by ACIP for all immunocompetent persons age 60 or older. However, in 2014, only 27.9% of adults eligible for this vaccine reported receiving the vaccine (MMWR Surveill Summ. 2016. 131. 320-330).

    • The vaccine is thought to boost immunity for years; data waning immunity after 5 - 11 years (J Infect Dis. 2016. 213. 1872-1875).

    • The vaccine is not recommended at age 50, even though licensed for use at age 50, based on a Markov model which shows that it is not cost-effective at age 50, with an estimated cost of > $300,000 per QALY (Ann Intern Med. 2015. 163. 489-497).

    • The vaccine must be stored at 5 degrees Fahrenheit (as it does not contain preservative), and the dose is 0.65 ml.

    • The Zostavax shingles vaccine is derived from the same virus as the chickenpox vaccine (Varivax), but Zostavax is 14 times more potent.

    • In a RCT in 38,546 immunocompetent men and women, mean age 69, the vaccine group after 3 years had a 51% lower incidence of shingles, a 66% lower incidence of postherpetic neuralgia, and a 61% lower burden of disease compared to the placebo group (N Engl J Med. 2005. 352. 2271-2284). Vaccination-related serious adverse events (for 42 days post vaccination) and deaths were monitored in all participants – serious adverse events were reported in 1.4 % of vaccine recipients and 1.4% of placebo recipients. Minor adverse events and hospitalizations were monitored in a nonrandomized sample of 6616 participants in the large study who volunteered to participate in a substudy - local inoculation side effects were reported in 48 % of these vaccine recipients and 16% of these placebo recipients. Rates of hospitalization and death did not differ between the two groups at mean follow up of 3.39 years, leading to the conclusion that safety of the zoster vaccine is very good (Ann Intern Med. 2010. 152. 545-554 and editorial 609-611).

    • In a retrospective cohort study of individuals enrolled in Kaiser Permanente Southern California health plan, among immunocompetent community dwelling adults age 60 years or older, receipt of the vaccine associated with a lower incidence of herpes zoster. Thus, efficacy in the ideal conditions of a RCT confirmed by data “in the field” (JAMA. 2011. 305. 160-166).

    • Cost of vaccine is approximately $223 in 2018,

    • In a study in 112 healthy adults aged 59 to 86, those who did 40 minutes of tai chi 3 times a week for four months prior to vaccination showed an immune response to the vaccine at 2 months post vaccination nearly twice as strong as the immune response in the control group (J Am Geriatr Soc. 2007. 55. 511-517).

  • Shingrix - Herpes zoster subunit vaccine (HZ/su) - FDA approved on October 20, 2017 and recommended by ACIP on October 25, 2017

    • Contains recombinant varicella-zoster virus glycoprotein E with a novel adjuvant (ASO1B) designed to improve CD4+ T-cell-mediated immune responses (Editorial. N Engl J Med. 2016. 375. 1079-1080).

    • Recommended by ACIP (in place of Zostavax, or in addition to Zostavax) for all immunocompetent adults age 50 an older (MMWR 1/26/18).

    • Two-does vaccine approved by FDA on July 26, 2021 for adults who are immunosuppressed or with compromised immunity, who are at high risk for the infection

    • Cost in 2018 of $280, as compared with $223 for Zostavax.

    • Practical considerations

      • Can be stored in a refrigerator, as opposed to a freezer.

      • Requires two doses, with the second dose to be administered 2 - 6 months after the first dose.

      • Side effects are common - approximately 80% of patients experience injection-site and systemic reactions within 7 days of injection.

    • In a RCT of 13,900 immunocompetent participants in 18 countries age 70 or older, at median follow up of 3.7 years, vaccine efficacy was 91.3% against herpes zoster (occurrence in 23 vaccine recipients as compared with 223 placebo recipients) and 88.8% against postherpetic neuralgia. Participants received two doses intramusculrar, 2 months apart (N Engl J Med. 2016. 375. 1019-1032).

    • In a prior RCT of individuals age 50 or older, vaccine efficacy was reported as 97.2% at a mean follow up of 3.2 years. 24% of participants in this trial were age 70 or older, and efficacy in this older subgroup was 97.9% (N Engl J Med. 2015. 372. 2087-2096).

    • An cost-effectiveness study conducted by researchers independent of the manufacturer of the vaccine concluded that cost is between $10,000 and $47,000 per QALY (Ann Intern Med. 2019. 170. 380-388 and editorial 414-417).

Smallpox

  • 48,164 annual cases prior to vaccine (MMWR. 1999. 48. 243); 29,005 annual cases 1900-1949 with 337 annual deaths (JAMA. 2007. 298. 2155-2163); 0 cases in 2005 (MMWR. 2007. 54. 2); 0 cases in 2006 (MMWR. 2007. 56. 33).

  • Universal vaccination recommended in the early 1900’s

  • 80 - 85% community immunity required for ‘herd immunity.’

Tetanus

  • 1314 annual cases prior to vaccine (MMWR. 1999. 48. 243); 580 annual cases 1947-1949 with 472 annual deaths (JAMA. 2007. 298. 2155-2163); 27 cases in 2005 (MMWR. 2007. 54. 2); 41 cases in 2006 (MMWR. 2007. 56. 33).

  • Disease of the nervous system mediated by an endotoxin of the bacterium Clostridium tetani.

  • Vaccine developed between 1906 and 1946; universal vaccination recommended in 1940’s, with DPT combination vaccine available in 1946.

  • Vaccine believed to be nearly 100% effective.

  • In 2006 in the US, only 85.2% of 19-35 month olds fully vaccinated with DTP (CDC data), compared with 94% in Canada and 98% in Mexico (WHO data).

  • Local reactions to the vaccine are common; severe reactions are extremely rare.

  • Seroprevalence studies support the current policy of giving boosters every 10 years.

  • Clinical epidemiologic data indicate that a single booster at age 65 is nearly as effective at preventing tetanus as boosters every 10 years and the cost/year of life saved is $4500 vs. $145,000 (J Gen Intern Med. 1993. 8. 405-412).

  • Emphasis should be on administering the primary series at 0, 1, and 6 months for adults without knowledge of receiving the primary series as a child, boosters for tetanus-prone wounds, and boosters at age 65.

  • The basis of the discrepancy between seroprevalence studies and epidemiologic data is presumably immune memory which is effective even though it cannot be measured serologically, and this is relevant to public policy discussions regarding boosters for hepatitis B and pneumovax (N Engl J Med. 1993. 328. 1252-1258).

  • For many years, only a Td toxoid booster was recommended in adults, but due to the resurgence of pertussis, and a new acellular pertussis vaccine which is safe in adults, booster with tetanus, diphtheria, and pertussis is now recommended for some adults (see details just above under category of ‘pertussis’).

Varicella 

  • Approximately 4 million annual cases prior to vaccine, with an average of 115 annual deaths from varicella (MMWR. 1999. 48. 243); 32,242 cases in 2005 with 3 deaths (MMWR. 2007. 54. 2); 48,445 cases in 2006 (MMWR. 2007. 56. 33).

  • Universal vaccination introduced in 1995.

  • Recommended for susceptible adults (i.e. those without a history of disease).

  • Should not be given to pregnant women.

  • Two doses 4-8 weeks apart.

  • Surveillance data in a population of 350,000 subjects showed that the annual rate of breakthrough varicella is 1.6 cases per 1000 person years within 1 year of vaccination, 9.0 cases per 1000 person years at 5 years post vaccination, and 58.2 cases per 1000 person years at 9 year post vaccination (N Engl J Med. 2007. 356. 1121-1129).

Enhancement of immune system response to immunization

  • DMG (dimethylglycine) 120 mg/day shown to boost antibody response to immunization in healthy volunteers (Graber CD et al. J Infect Dis. 1981. 143. 101-145).

  • Multivitamin for at least one week pre-immunization and two weeks post-immunization may be beneficial

  • Prebiotics and probiotics - a systematic review and meta-analysis of 9 RCTs (N = 623) showed that those participants who took either probiotics or prebiotics demonstrated enhanced immunogenicity following influenza vaccines.  The odds ratio for seroprotection against H1 N1 was 1.83, the odds ratio for seroprotection against H3 N2 was 2.85, and the odds ratio for seroconversion against influenza B was 2.11.  The review paper in which the study is cited does not include any further information such as the duration of prebiotic/probiotic treatment (Lei WT et al. Nutrients.  2017. 9. 1175).

  • Tai chi - in a study in 112 healthy adults aged 59 to 86, those who did 40 minutes of tai chi 3 times a week for four months prior to vaccination showed an immune response to the vaccine at 2 months post vaccination nearly twice as strong as the immune response in the control group (J Am Geriatr Soc. 2007. 55. 511-517).

  • Vitamin C just before the vaccination may have an antibody-stimulating effect (consider 500 – 1000 mg, either in the form of sodium ascorbate powder mixed fruit juice or liposome-encapsulated gel mixed in yogurt).

  • Vitamin D supplementation (such as at a dose of 2000 IU daily) has been shown to enhance the effectiveness of tetanus toxoid immunization (Eur J Clin Nutr. 2011; 65:329–334) and influenza vaccine (Front Immunol. 2019; 10:65).

  • Zinc citrate or zinc picolinate 30 mg daily if zinc deficiency is clinically suspected

Minimize (theoretically) adverse reactions to immunization

  • Homeopathic Ledum 30C, 5 pellets just before and an hour after the shot (use 3 pellets, crushed between 2 spoons to administer to infants)

  • Homeopathic Thuja 30C, 5 pellets the next day if adverse reaction (200C if severe reaction; use 3 pellets, crushed between 2 spoons to administer to infants).

  • Vitamin C just before the vaccination may have a toxin-neutralizing effect (consider 500 – 1000 mg, either in the form of sodium ascorbate powder mixed with fruit juice or liposome-encapsulated gel mixed in yogurt).

  • Vitamin C, adjusting the dosing to bowel tolerance pre and post vaccination may reduce the possibility of an adverse effect (Levy TE. OMNS. 2012. 8. 7).

  • Methylfolate may reduce the risk of reacting to adjuvants in vaccines, for those with MTHFR polymorphism.

  • Detoxification support (such as NAC or liposomal glutathione, intestinal binders) may facilitate elimination and excretion from the body of additional components in vaccines, such as adjuvants, additives, preservatives, stabilizers, and inactivating chemicals (see section at very top of this web page on additional components of vaccines).

  • Immune modulation starting 2 weeks post vaccination might reduce the risk of autoimmunity and inflammatory syndrome post vaccination. Cytoquel® (manufactured by Researched Nutritionals) is a multi-ingredient supplement which modulates immune system function.

Resources

Page Updated October 24, 2024