Vaccines




Acknowledgment


I would like to thank Kent J. Stock who wrote this chapter for the previous edition and whose work contributed greatly to this text.




Historical background


Immunization is the method of artificially inducing immunity to prevent the development of disease. The artificial induction of immunity was first demonstrated by Edward Jenner in 1796 after he observed that milkmaids who had contracted cowpox were immune to smallpox. He developed the practice of vaccination, inoculating fluid from cowpox lesions into the skin of susceptible individuals. Inoculated individuals typically developed only mild illness. Vaccination in the United States started shortly thereafter, and the first law to require smallpox vaccination was passed in 1809 in Massachusetts. In a ruling that would become the basis for public health laws to this day, the Supreme Court in 1905 upheld the rights of states to enforce compulsory vaccination laws, with Justice Harlan writing in the majority opinion that “the possession and enjoyment of all rights are subject to such reasonable conditions as may be deemed by the governing authority of the country essential to the safety, health, peace, good order and morals of the community.”


Vaccines have proven extremely effective at reducing the global burden of naturally occurring disease. Measles, for example, has been virtually eliminated among those vaccinated in the United States, but continues to devastate displaced populations in developing countries where immunization is less prevalent. In disaster situations vaccination programs are of the utmost importance to prevent outbreaks of infectious diseases.


More concerning, particularly in recent years, has been the use of viruses and bacteria as weapons of terrorism and war. The Biological and Toxin Weapons Convention was established in 1972 and produced a treaty that prohibits the development, production, stockpiling, and acquisition of biologic weapons. This was the first comprehensive, international effort to ban biologic and chemical weapons since the Geneva Protocol in 1925, and it was the first international treaty to ban an entire class of weapons. The treaty was signed by 144 nations, including the United States and the Soviet Union, which had the largest stockpiles of such weapons at the time. To this day, however, there is no mandatory monitoring program in place.


On October 4, 2001, a case of inhalational anthrax was reported in Florida. Epidemiologists at the Centers for Disease Control and Prevention (CDC) later identified and confirmed 22 cases: 11 cases of inhalational anthrax and 11 cases of cutaneous anthrax. The dissemination of these anthrax spores via letters through the U.S. mail appeared to be an intentional act of bioterrorism. In the aftermath of the Al-Qaida attacks on the World Trade Center and Pentagon buildings, this act illustrated a vulnerability to terrorist attacks involving biologic weapons. In response to the terrorist attacks, the U.S. government passed the USA Patriot Act in October 2001 and the Public Health Security and Bioterrorism Preparedness and Response Act in June 2002. These acts created the Department of Homeland Security and empowered the Department of Health and Human Services (DHHS) to begin efforts to protect the civilian population against future attacks with biologic weapons by enhancing surveillance and promoting preparedness.


DHHS, in conjunction with the CDC and National Institutes of Health, convened members of the research community to discuss the development of a research agenda and strategic plan for biodefense research. These efforts to counter bioterrorism focused on a group of microbes that included Yersinia pestis (plague), Francisella tularensis (tularemia), Bacillus anthracis (anthrax), Variola major virus (smallpox), Clostridium botulinum (botulism), and the hemorrhagic fever viruses. Smallpox, eradicated in 1977 from natural transmission, was particularly feared because of its high mortality rate, the absence of specific therapy, and the highly susceptible general population. Current CDC plans focus on targeted vaccination, contact tracking, and isolation and quarantine. There was initial debate on whether the entire population should be vaccinated to eliminate the threat of a future attack, or whether to institute a targeted vaccination program only after an attack occurs or if the likelihood of an attack is deemed high by government officials. CDC officials decided to support a “ring vaccination” approach after a case of smallpox was identified. This vaccination approach focuses on a surveillance and containment strategy. It involves the identification of smallpox cases, isolating those individuals, and vaccinating contacts and household contacts of those contacts. The plan does not recommend mass vaccination in response to a documented case.


A well-developed, country-level vaccination program is probably the best protection against an intentional or spontaneous outbreak, because the infrastructure of the vaccine program can be rapidly adapted to meet the new challenge. For example, if there were an outbreak of a new strain of influenza in the United States, the yearly flu vaccine may provide some immunity, and the well-developed cold chain and delivery mechanism in place could be scaled to meet the needs.




Immunity


Immunization can be induced via active or passive methods. Active immunization typically involves the administration of a vaccine, such as the rabies vaccine, to induce the host to produce an immune response against a particular microorganism. Passive immunization refers to the practice of providing temporary protection by passively transferring an exogenously produced antibody, such as rabies immune globulin, to a susceptible host. Immunizing agents include vaccines, toxoids, antitoxins, and antibody-containing solutions.


The initial response of the immune system to the introduction of an antigen occurs after the primary exposure. Circulating antibodies do not typically develop for 7 to 10 days. If an antigen is presented for a second time, an exaggerated humoral- or cell-mediated response occurs, called an “amnestic response.” These amnestic responses usually result in antibody formation within 4 to 5 days.


There are multiple determinants of immunogenicity including the physiological state (e.g., nutrition, immune status, age) and the genetic characteristics (e.g., major histocompatibility complex polymorphism) of the host, the manner in which the immunizing agent is presented (e.g., route, timing of doses, use of adjuvants), and the composition and degree of purity of the antigen.




Vaccines


The ideal vaccine should possess the following characteristics :




  • It should be easy to produce in well-standardized preparations that are readily quantifiable and stable in immunobiological potency.



  • It should be easy to administer.



  • It should not produce disease in the recipient or susceptible contacts.



  • It should induce long-lasting (ideally permanent) immunity that is measurable by available and inexpensive techniques.



  • It should be free of contaminating and potentially toxic substances.



  • It should cause minimal adverse reactions that are minor in consequences.



Current vaccines do not typically meet all of these criteria. Most possess limited efficacy or have unwanted side effects.


Vaccines typically consist of live-attenuated or killed-inactivated microbiological agents. Many viral vaccines contain live-attenuated virus (e.g., measles, mumps, rubella, oral polio). The vaccines for some viruses and most bacteria are killed-inactivated, subunit preparations or are conjugated to immunobiologically active proteins (e.g., tetanus toxoids). Live-attenuated vaccines tend to elicit a broader and more durable immunological response on behalf of the recipient. Killed-inactivated vaccines, which typically have a lesser antigenic effect, require booster vaccinations.


Currently licensed vaccines are generally both effective and safe; however, adverse events are associated with vaccine administration. Adverse events can be both trivial and life threatening. Examples include injection site reactions, fever, irritability, and hypersensitivity reactions. Administration of live viruses can sometimes lead to disseminated infection and therefore is contraindicated in immunocompromised populations and when the risk of disease is low.


Oral polio vaccine is one such live-attenuated vaccine that, while creating more immunity than the dead virus injected form, is no longer used in developed countries because in the setting of low disease prevalence, the risk of the vaccine inducing clinical polio was greater than the benefit. The development of the oral polio vaccine had a profound initial impact on childhood morbidity and mortality. In the early 1950s there were approximately 16,000 cases of polio each year in the United States, but after vaccination the last naturally occurring case was in 1993. From 1980 through 1999 in the United States when oral polio vaccine was still in use, there were 162 confirmed cases of paralytic polio and 154 of these cases were vaccine-associated. The United States has now transitioned to the dead virus injectable form that is not able to transform. The oral live-attenuated polio vaccine, although able to transform, is still used internationally because of its increased immunogenicity. On the whole it is thought to prevent disease, despite outbreaks such as occurred in 2006 when 70 children in Nigeria were found to have vaccine-associated paralytic polio.


The National Childhood Vaccine Injury Act was passed by Congress in 1986. This act required the reporting of certain vaccine adverse events to the secretary of the DHHS. It also led to the creation of the Vaccine Adverse Events Reporting System. The system’s primary function is to investigate and study new vaccine adverse events or changes in the frequency of known vaccine adverse events. The reporting system has helped identify rare adverse events, including intussusceptions associated with the initial rotavirus vaccine, ischemic cardiac events among smallpox vaccine recipients, and viscerotropic and neurotropic disease after yellow fever virus administration.


Vaccine Storage


Maintaining a cold chain from manufacture to delivery of a vaccine is usually the most difficult part of a vaccination program. Whereas each vaccine should be evaluated for specific requirements, as a general rule the cold chain should be able to maintain temperatures between 2 and 8 °C without allowing freezing ( Table 29-1 ). The live-attenuated influenza vaccine and varicella are two exceptions to this rule and are stored frozen at − 15 °C. Stand-alone refrigerators are preferred to combination freezer/refrigerator units because the former has a more uniform temperature throughout the area where vaccines will be stored. Certain vaccines contain an aluminum adjuvant that precipitates when exposed to freezing temperature, and if this precipitate is noted then the vaccine should be discarded. Not all vaccines have this property, however, and a normal appearance does not assure reliability. According to the CDC, temperatures should be documented twice daily and a thermometer with an accuracy of ± 0.5 °C used. It is important that the thermometer have a certificate of traceability and calibration testing.



Table 29-1

Vaccine Storage Temperature Requirements


















35-46 °F (2-8 °C) ≤ 5 °F (− 15 °C)
Instructions Vaccine Instructions Vaccine
Do not freeze or expose to freezing temperatures.


Contact state or local health department or manufacturer for guidance on vaccines exposed to temperatures above or below the recommended range.
Diphtheria-, tetanus-, or pertussis-containing vaccines (DT, DTap, Td)
Haemophilus conjugate vaccine (Hib) *
Hepatitis A (HepA) and hepatitis B (HepB) vaccines
Inactivated polio vaccine (IPV)
Measles, mumps, and rubella (MMR) vaccine in the lyophilized (freeze-dried) state
Meningococcal polysaccharide vaccine
Pneumococcal conjugate vaccine (PCV)
Pneumococcal polysaccharide vaccine (PPV)
Trivalent inactivated influenza vaccine (TIV)
Maintain in continuously frozen state with no freeze-thaw cycles.

Contact state or local health department or manufacturer for guidance on vaccines exposed to temperatures above the recommended range.
Live attenuated influenza vaccine (LAIV)
Varicella vaccine

* ActHIB (Aventis Pasteur, Lyon, France) in the lyophilized state is not expected to be affected detrimentally by freezing temperatures, although no data are available.


MMR in the lyophilized state is not affected detrimentally by freezing temperatures.



In many instances refrigeration may not be available on transport to the end user. If nonfrozen vaccines are to be brought into the field the following protocol is recommended :



  • 1.

    Use a hard-sided insulated cooler with walls at least 5 cm (2 inches) thick.


  • 2.

    First place at least a 5-cm (2-inch) layer of coolant packs that have been left at room temperature for 1 to 2 hours in the base of the container. Completely frozen coolant can freeze vaccine.


  • 3.

    Place an insulating barrier such as bubble wrap on top of the coolant packs.


  • 4.

    Then place a thermometer as well as vaccines on insulating barrier.


  • 5.

    Place another layer of insulation on top of the vaccines and then a second 5-cm (2-inch) layer of coolant packs.


  • 6.

    Finally, place a layer of insulating material on top of coolant packs and firmly secure cooler lid.





Current practice


Potential Bioterrorism Agents


The CDC has designated three categories of biologic agents according to their potential as weapons of terrorism. Category A agents were given the highest priority because they are easily disseminated or transmitted, associated with high mortality rates, can cause panic and social disruption, and require special action for public preparedness. Category B agents are moderately easy to disseminate, cause moderate morbidity and low mortality, and require enhanced diagnostic capacity and disease surveillance. Category C agents include emerging pathogens that have the potential for becoming biologic weapons in the future.


Category A


Anthrax ( Bacillus anthracis )


Anthrax is a potentially devastating bioterrorism weapon and is discussed in detail in Chapter 124 . During the 2001 anthrax events, a total of 11 cases of inhalation anthrax were identified with a case fatality rate of 45%, despite intensive care management. BioThrax is the only human vaccine for the prevention of anthrax in the United States. Licensed in 1970, the vaccine was formerly known as Anthrax Vaccine Adsorbed (AVA). The vaccine is prepared from a cell-free culture filtrate of a nonencapsulated, attenuated strain of B. anthracis . The most recent immunization schedule from 2008 involves five immunizations. The vaccine is administered intramuscularly in a 0.5-mL dose at 0 then 4 weeks and 6, 12, and 18 months, with an annual booster recommended thereafter. The available vaccine is recommended for select laboratory workers and military personnel.


In 1998, the U.S. Department of Defense recommended vaccinating military recruits against anthrax; since then about 8 million military personnel have been vaccinated. Opposition by some recruits was voiced because of a fear of unwanted side effects, and currently only personnel operating in high risk areas are mandated to receive the vaccine. Adverse events from vaccination include injection site reactions, fever, chills, myalgia, and hypersensitivity reactions.


The vaccine has proven effective for the prevention of cutaneous disease in adults, but no conclusive evidence exists that it is protective against the more dangerous inhalation form. There are studies in nonhuman primates, however, that suggest it confers protection from inhalational disease as well. In the event of an inhalation anthrax event the CDC recommends 60 days of appropriate antimicrobial prophylaxis, such as ciprofloxacin, combined with three doses of vaccine administered at 0, 2, and 4 weeks postexposure. In high risk exposures, it is recommended that both pregnant women and children adhere to the same schedule.


Botulism ( Clostridium botulinum )


There are four major types of botulism: foodborne, wound, adult colonization, and infantile ( Clostridium botulinum is discussed more thoroughly in Chapter 154 ). There is also theoretical concern that botulism could be aerosolized and cause an inhalational form of disease. In each case the bacteria forms a toxin that is carried in heat-resistant spores and causes a neuroparalytic illness. There is no person-to-person transmission. Therapy for each includes passive immunization with antitoxin and supportive care. From the standpoint of a bioterrorism threat, contamination of the food supply causing the foodborne form of illness is the most concerning. Unusually large numbers of patients presenting with acute, descending flaccid paralysis and prominent cranial nerve involvement should be considered a sign of a potential bioterrorism event. Symptom onset is usually within 36 hours of exposure, however, a latency period of up to 10 days is possible. This delay in onset may make it more difficult to identify botulism as the causative agent event early on, when the antitoxin is most useful. A retrospective study demonstrated that the administration of antitoxin within 24 hours of onset of symptoms was associated with an overall mortality rate of 10%, compared with 15% in patients in whom antitoxin was administered after 24 hours of symptoms and 46% in patients who did not receive antitoxin at all.


Heptavalent botulinum antitoxin (HBAT) is the only available antitoxin in the United States for foodborne and wound botulism and is available through the CDC. Human-derived botulinum (BIG-IV) is indicated for use in cases of infant botulism. Treatment only prevents progression of paralysis because the antitoxin neutralizes toxin molecules that have not yet bound to nerve endings. While many patients will recover when the neuromuscular connections regenerate, this process may take up to two months of ventilator support and stress our health care resources. There is no licensed botulism vaccine.


Smallpox ( Variola major )


The last case of endemic smallpox in the United States occurred in 1949 and worldwide in 1977 in Somalia. With no natural reservoir or host other than humans, the only known stocks of variola virus are in research laboratories in the United States and Russia. Concern for its use as an agent of bioterrorism remains especially high because of fear that not all isolates were properly guarded during the chaotic fall of the USSR. Furthermore, the United States and world population lacks immunity to smallpox, because routine vaccination against the virus ceased in the United States in 1972 and worldwide in 1982.


Unfortunately, the onset of symptoms begin vaguely, with fever and myalgias after an incubation period of 7 to 17 days. After a few days of illness, macular/papular lesions that are most prominent on the face and extremities develop into characteristic vesicular and then pustular lesions. Groups of lesions at different stages of development across the body are classic and help differentiate smallpox from chickenpox. Patients remain contagious until all lesions are crusted and separated from the skin.


Smallpox can be spread from person to person by droplet, but can also be spread by contact, as demonstrated by its use as an agent of bioterrorism during the 1700s, when infected blankets were distributed to Native American populations with devastating effect. Among nonimmunized populations the case fatality rate in the 1960s was about 30%, and it is unclear if this would be substantially different with modern intensive care.


When administered early in the incubation period the vaccine is believed to be highly efficacious, , and the CDC now stocks enough for every American. The vaccine is administered with the use of a bifurcated needle. A droplet of vaccine is held by capillary action between the two tines. The needle is introduced into the epidermis and 15 perpendicular strokes are rapidly made in a 5-mm area. A skin lesion known as a Jennerian pustule forms with an area of crusting and edema at the site of inoculation about 5 days after inoculation and represents successful vaccination. The lesions scab and leave a scar.


The smallpox vaccine is a live virus vaccine made from the related vaccinia virus. It is considered safe, but adverse events have been described. Vaccination programs for smallpox among military personnel and health care providers have been limited because the public has come to see the vaccine itself as potentially more harmful than the possibility of disease. Injection site pain and myalgia and other minor side effects are common. Complications include postvaccinial encephalitis (12.3/1 million primary vaccinations), progressive vaccinia (1.5/1 million primary vaccinations), eczema vaccinatum (38.5/1 million primary vaccinations), generalized vaccinia (241.5/1 million primary vaccinations), inadvertent inoculation (529.2/1 million primary vaccinations), rashes (1/3700 vaccinated), Stevens-Johnson syndrome (rare), and myopericarditis (< 1/12,000 vaccinated persons). , Death occurs as a result of life-threatening reaction to the vaccine in about 1 per 1 million primary vaccinations. Vaccinia immune globulin (VIG) and cidofovir may be used to treat patients with serious adverse reactions. In the event of a bioterrorism event any exposed person, including pregnant women and children, should be vaccinated. Smallpox is discussed in more detail in Chapter 147 .


Plague ( Yersinia pestis )


Rodents are the primary natural reservoir for plague, and it is typically spread to humans by the bite of a flea. In the 1300s a plague pandemic caused the death of about one third of all Europeans. During that same period were the first reports of its use as a biological weapon when catapults were used to launch corpses of those killed by plague into cities under siege. In World War II the Japanese dropped infected fleas from airplanes, causing outbreaks in Chinese villages. It is suspected that both the United States and Russia have aerosolized versions that no longer require fleas for transmission. There are three main categories of plague: bubonic, bloodstream septicemic, and pneumonic. The vector of exposure is primarily responsible for determining which clinical manifestations will predominate. For example, inhalational exposure will cause pneumonic plague. Clinically, the disease resembles a rapidly progressing pneumonia that can develop into acute respiratory distress syndrome (ARDS). Antibiotics such as streptomycin and gentamicin, when administered early in the course of disease, are effective in conjunction with aggressive supportive care to reduce the case fatality rate to 5% to 14%. There is no current vaccine available. However, until 1999 there was a formaldehyde-killed whole-cell bacilli vaccine available. It was not effective against pneumonic plague, but it did have some protective effect against bubonic disease. , Research is ongoing regarding a new vaccine. See Chapter 125 for a more thorough discussion of Yersinia pestis .


Tularemia ( Francisella tularensis )


In the 1950s the U.S. military aerosolized F. tularensis for use as a biological weapon, and it is speculated that Russia has similar stores. Inhalation tularemia causes a nonspecific febrile illness without prominent respiratory symptoms or findings in the early phase. Antibiotics are generally effective therapy, along with supportive care. There is an experimental vaccine carried by the U.S. Department of Defense and under review by the Food and Drug Administration. Vaccination is not currently recommended for postexposure prophylaxis because of its limited efficacy and available alternative treatment. More information on Francisella tularensis can be found in Chapter 126 .


Hemorrhagic fever viruses


Hemorrhagic fever viruses are discussed in more detail in 142 , 143 , 144 , 145 . They are divided into four distinct families of viruses that each cause fever and a bleeding diathesis. The four families (including examples) are Filoviridae (Ebola), Arenaviridae (Lassa virus), Bunyaviridae (hantavirus), and Flaviviridae (dengue and yellow fever). These viruses are typically spread by arthropod vectors, aerosols, or direct contact. Human to human transmission is possible for most, with the notable exception of Flavivirida viruses. Research on the weaponization of these viruses was performed by both the USSR and the United States. There are no licensed vaccines for any of the hemorrhagic fever viruses, except for yellow fever. The yellow fever vaccine was initially licensed in 1953. It is a live-attenuated vaccine that is highly effective in travelers to endemic areas. It is not recommended for postexposure prophylaxis because of the virus’s short incubation period.


Category B


Food safety threats (e.g., Salmonella species, Chapter 134 ; Escherichia coli O157:H7, Chapter 139 ; Shigella , Chapter 133 )


Typhoid is predominantly a concern in developing countries. There are three typhoid ( Salmonella typhi ) vaccines that are currently licensed for use in the United States. The first is an oral live-attenuated vaccine that was licensed for use in 1990. It is indicated for children age 6 and older, as well as for adults. Individuals ingest one enteric-coated capsule every other day for a total of four doses. The manufacturer recommends a new complete series every 5 years. The oral vaccine is associated with minimal unwanted side effects. Reported side effects include abdominal discomfort, nausea, vomiting, fever, headache, and rash. The second available option is parenteral heat-phenol-inactivated vaccine that was first licensed for use in 1917. This vaccine is very effective, but has higher rates of adverse reactions and requires two injections 4 weeks apart. The third option is a Vi capsular polysaccharide vaccine, which is indicated for individuals age 2 and older. The main advantage of this vaccine is that it is administered as a single intramuscular injection. Booster doses are recommended by the manufacturer every 2 years. Adverse effects associated with the parenteral vaccine include fever (0% to 1%), headache (1.5% to 3%), and injection site reactions (7%). The demonstrated efficacy of these vaccines ranges from 50% to 80% after a primary series. Immunization is currently recommended for travelers to endemic areas, people with an exposure to a documented Salmonella typhi carrier, and laboratory workers with frequent contact with S. typhi . General contraindications include children younger than 2, pregnant women, and people with a history of a hypersensitivity reaction to the vaccine. The oral Ty21a vaccine should not be administered to individuals actively taking antibiotics, especially sulfonamides or mefloquine. One should allow the individual to stop taking these medications for at least 24 hours before administering the vaccine. The oral vaccine, which is a live-attenuated virus, should not be administered to immunocompromised individuals. No human vaccine is currently available for the prevention of illness caused by Escherichia coli O157:H7, Shigella dysenteriae , or salmonellosis.


Water safety threats (e.g., Vibrio cholerae , Chapter 132 )


There are now multiple oral cholera vaccines available, including next generation vaccines such as the rBS-WC vaccine. In a mass immunization campaign from 2003 to 2004 in a region of Mozambique where cholera is endemic, the rBS-WC vaccine was shown to decrease rates of cholera by 78%. While the World Health Organization and CDC do not generally advise immunization for individuals traveling to or from cholera-infected regions, vaccination may play a role in preventing and containing outbreaks among vulnerable populations.


For the other Category B diseases, no human vaccine is currently available: Q fever ( Coxiella burnetii , Chapter 128 ), brucellosis ( Brucella species, Chapter 127 ), glanders ( Burkholderia mallei , Chapter 136 ), melioidosis ( Burkholderia pseudomallei , Chapter 137 ), viral encephalitis (alphaviruses, e.g., Venezuelan equine encephalitis, eastern equine encephalitis, western equine encephalitis, Chapter 140 ), typhus fever ( Rickettsia prowazekii , Chapter 129 ), toxins (e.g., ricin, Chapter 158 ; epsilon of Clostridium perfringens , Chapter 155 ; staphylococcal enterotoxin B, Chapter 153 ), and psittacosis ( Chlamydia psittaci , Chapter 138 ). Similarly, no human vaccine is available for Category C emerging threats: Nipah virus ( Chapter 151 ) and hantavirus ( Chapter 150 ).


Vaccinations for displaced persons


Of foremost concern in a refugee camp setting is control of communicable diseases. Vaccinations, along with proper water sanitation settlement design, are necessary to achieve this goal. Outbreaks of measles can have a case fatality rate as high as 10% to 20% and spread rapidly by droplet transmission. Measles vaccination campaigns should be undertaken by response teams when predisaster vaccination coverage is less than 90% or is unknown. A measles immunization program along with vitamin A supplementation is recommended in emergency settings, with first priority given for children from the ages of 6 months to 5 years, and then if supplies are available, children up to 15 years old should also be immunized.


Cholera epidemics from the Democratic Republic of the Congo to Haiti have demonstrated the devastation that it can cause among displaced persons. While the prime treatment for cholera remains oral rehydration therapy (ORT), zinc supplementation, and antibiotics, vaccination is becoming a viable adjunct in combating this disease.


The decision on what vaccines to provide to displaced populations is complex and depends on both general risk factors of the population and disease-specific risk factors. General risk factors for a population to consider are nutritional status, burden of chronic diseases, age distribution, access to health services, and finally sanitation, water supply, and degree of overcrowding. Disease-specific factors that must also be considered include the environmental conditions allowing for transmission, population immunity (innate or vaccine induced) against the disease, and burden of the specific disease prior to emergence. Each of the above parameters are graded as low, medium, or high risk based on criteria developed by the World Health Organization (WHO) and then entered into a classification table shown in Table 29-2 . This can help inform the decisions on whether a particular vaccine should be implemented.


Aug 25, 2019 | Posted by in EMERGENCY MEDICINE | Comments Off on Vaccines

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