In October 2013, Korea's Ministry of Food and Drug Safety (MFDS) granted approval for the administration of the 13-valent pneumococcal conjugate vaccine (PCV13) to adults 18 years of age or older.

The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been widely used for a long time. It contains 23 kinds of serotypes and is known to have some preventive effect against invasive pneumococcal disease (IPD) [1, 2]. However, PPV23 has not been proved effective against pneumonia, and it has not been effective enough for patients with underlying diseases who are highly prone to developing pneumococcal disease. Furthermore, PPV23 can stimulate only T-cell independent immune response, which makes the duration of protection short, around 5 years, and it is not able to induce the herd immunity.

In contrast to PPV23, PCV13 induces an anamnestic reaction by stimulating a T-cell dependent immune response. It not only prevents IPD but also clearly decreases the occurrence of pneumonia, otitis media, and nasopharyngeal colonization of vaccine serotypes in children [1]. PCV13 has reduced more than 90% of antibiotic-resistant IPD caused by serotypes, among infants and children. Moreover, it is reported that the vaccine induces the herd immunity, in which adults who have not received it also see a decrease in the number of IPD cases [1]. A double-blind and randomized study (Community-Acquired Pneumonia Immunization Trial in Adults, CAPiTA) conducted on 85,000 adults aged 65 years and older found that vaccination with PCV13 reduced vaccine-type community-acquired pneumococcal pneumonia, vaccine-type nonbacteremic pneumococcal pneumonia, and vaccine-type IPD by 46%, 45%, and 75%, respectively [3]. In a clinical trial on adults over 18 years of age, PCV13 demonstrated superior or similar immunogenicity compared to PPV23, with similar rates of adverse reactions [4, 5, 6]. In a study conducted on patients with AIDS, PCV13 showed immunogenicity superior to PPV23 and demonstrated preventive effects against recurrence of IPD [7, 8].

Studies that conducted cost-effectiveness analyses of pneumococcal vaccines agree that the most important elements affecting the analysis are the level of herd immunity provided by PCV13 administration in children and the efficacy for nonbacteremic pneumococcal pneumonia. This indicates that if PCV13 administration in children does not induce enough herd immunity, but that the vaccine works better among adults in preventing nonbacteremic pneumococcal pneumonia, PCV13 may be more cost-effective than PPV23 for adults aged ≥65 years and high-risk groups. In fact, after the U.S. and some European countries introduced the protein-conjugated vaccine into the national immunization program (NIP) for children, IPD in those age groups decreased significantly, as well as among adults due to herd immunity. However, adults 65 years of age and older did not see such an evident decrease as the children did [9, 10]

The graph of IPD occurrence by age shows the shape of a U, which is high under the age of 5, then decreases, increasing again after the age of 50. In the U.S., serotypes contained in PCV13 cause one-third of cases of IPD, and serotypes only contained in PPV23 cause 25% of cases of IPD [11]. Among adults 19 years of age or older with immunocompromising conditions, 50% of IPD cases are attributed to PCV13 serotypes, whereas serotypes only contained in PPV23 are responsible for 21% of cases of IPD [12]. In Korea, it was found that 0.36 out of 1,000 inpatients 18 years of age or older had IPD. The fatality rate was reported to be around 30%, and both the number of patients and the fatality rate tended to be higher with older patients. Among IPD patients, 64.9% were found to have underlying disease [13]. According to research on serotype distribution of IPD among adults 19 years of age or older, before the introduction of PCV13, serotypes contained in PCV7, PCV13, and PPV23 accounted for 39.8%, 67.3%, and 73.4% of IPD, respectively [14]. However, after the introduction of PCV13, the serotype coverage rates for IPD decreased in both PCV13 and PPV23, and the difference between the two vaccines as the cause of the disease ranged between 15 and 20% [2]. Also, there was an increase in the proportion of IPD cases caused by serotypes not contained in any vaccine.

In 2014, in its revised guidelines on pneumococcal vaccination, the U.S. Advisory Committee on Immunization Practice (ACIP) advised that all adults 65 years of age and older to receive PCV13, followed by PPV23 [15]. This was the Committee's conclusion after considering the following factors: the insufficient level of herd immunity among adults aged 65 years and older that is induced from vaccinating children; the proven efficacy of PCV13 in CAPiTA against pneumococcal pneumonia; and cost-effectiveness analysis of the strategy.

Pneumonia is a growing cause of death in Korea, and S. pneumoniae is reported as the most common cause of the disease. This necessitates administration of PCV13, which prevents non-invasive pneumococcal disease including pneumonia. PVC13 and PPV23 should be given consecutively because the gap of serotype coverage for pneumococcal disease is widening between PCV13 and PPV23, as in the U.S. and Europe. However, there is insufficient evidence to recommend consecutive administration of PCV13 and PPV23 to all persons 65 years of age and older across the board as there has been no assessment of the cost-effectiveness of PVC13 in this age group.

When administering PCV13 and PPV23, another area that requires consideration is the immune response according to the order in which the vaccines are administered. Booster effect may be induced if PCV13 is administered first, while hypo-responsiveness occurs if PPV23 is given first. Thus, it may be more beneficial to administer PCV13 first [16, 17].

The Committee on Adult Immunization has stated that one of the PVC13 or PPV23 should be given for healthy adults aged 65 years and older. However, the Committee has recommended that adults in the same age group with chronic medical conditions should receive PCV13 first, followed by PPV23 6 to 12 months later, because these individuals have a high risk of severe pneumococcal disease caused by various serotypes. However, PCV13 and PPV23 should not be administered at the same time and there must be an interval of at least 8 weeks between the administrations (Fig. 1).

Since 2013, the U.S. ACIP has recommended that women receive a Tdap vaccine during each pregnancy [18]. The U.S. has seen an increasing outbreak of diphtheria nationwide since the early and mid 2000s. Since 2006, the Committee had recommended that pregnant women without previous Tdap vaccine administration receive the vaccine right after pregnancy, as well as any family members or caregivers who would contact the newborn. However such a cocooning strategy did not turn out to be effective, and failed to protect newborns from being exposed to pertussis until the time when they received their first diphtheria-tetanus-acellular pertussis vaccine (DTaP) for infants, two months after birth. In June 2011, the U.S. ACIP sought to provide a remedy for the problem by advising women to receive the Tdap vaccine during pregnancy (after 20 weeks). However, only 2.6% of the advised women took the advice, making it difficult to assess whether the new guideline was effective. The number of pertussis patients jumped to 48,277 in 2012, two to three times higher than the average. Considering the disease burden of pertussis in newborns, the safety of the Tdap vaccine in adults, and the weakening of immunogenicity acquired from childhood vaccination over time, the ACIP decided to strengthen the guideline to advise women to receive the Tdap vaccine between 27 to 36 weeks of pregnancy regardless of their Td/Tdap vaccination history. The decision was based on the judgment that mothers can acquire antibodies through vaccination that would be passed down to newborns during pregnancy. The grounds for the judgment are as follows: vaccination after giving birth to the first child maintains a sufficient antibody titer not only for the mother but also for the child in the second pregnancy [19]; Tdap vaccination received at any point in pregnancy provides a high antibody titer in the body at the time of childbirth [20]; vaccination during the third trimester provides the highest concentration of vaccine-specific antipertussis antibodies transported from mother to infant [21]; and vaccination during pregnancy does not cause a critical adverse reaction in mothers or newborn infants [22]. Vaccination guidelines for family members and caregivers have been strengthened as well. In 2011, vaccination was recommended to adults 64 years of age and younger without previous vaccination history and adults older than 64 years of age if there is a child younger than 12 months in the household [23]. The guidelines in 2013 recommended vaccination to all adults without previous vaccination [24], and the 2014 edition expanded the range to the population group 11 years of age and older without previous vaccination, directly and indirectly strengthening the cocooning strategy [25].

In the UK, the number of pertussis cases was reported to be 8,819 in 2012, 10 times higher than in 2011, and 13 newborn infants died from the disease. Since 2013, the country has begun advising women to get vaccinated in every pregnancy, while the recommended time of vaccination-between 28 and 38 weeks gestation, ideally before 32 weeks-varies slightly from that in the U.S. [26]. Canada recommends that pregnant women receive a dose of vaccination right after delivery as the best plan or during the third trimester of pregnancy as the second-best plan, if they have had no previous Tdap vaccination in adulthood [27]. In Australia, the best recommendation is vaccination before pregnancy or right after childbirth, and the second-best is vaccination during the third trimester of pregnancy. The country recommends that women get vaccinated again even if they had received a Tdap vaccine before, if more than 5 years have passed since their last vaccination at the time of delivery [28].

Women are recommended to receive a dose of Tdap vaccine before pregnancy or right after delivery in the KSID's Tdap vaccine guidelines for pregnant women in its Adult Immunization 2^nd Edition. The guidelines are similar to those of the U.S. or the UK, as Adult Immunization 2^nd Edition was published before their guidelines were revised. The number of pertussis cases in Korea has increased in a similar manner to that of the U.S. [29]. The average was 11.4 per year from 1995 to 2008, but increased to 66 in 2009, 27 in 2010, and 97 in 2011. The number hit 230 in 2012 due to a pertussis epidemic in Jeollanam-do [30], but fortunately dropped to 45 in 2013. Currently, there is insufficient evidence to recommend that women receive vaccination in every pregnancy in Korea as in the U.S. and the UK, considering the pertussis dynamics in Korea, while the idea could be reconsidered depending on the pertussis trend and possible future epidemics. Therefore, recommendations regarding the Tdap vaccine for women will remain the same-women without previous Tdap vaccination should receive a single dose before pregnancy or right after delivery. However, pregnant women between 27 and 36 weeks gestation can be vaccinated, because there are solid grounds that support the benefits and safety of vaccination during pregnancy. Furthermore, as there is clear evidence that pertussis among family members can cause pertussis infection in infants, relevant government agencies should actively promote Tdap vaccination for parents and grandparents who have not received the vaccine previously. Primary healthcare professionals should be encouraged to help further the cause.

Males aged 9 through 15 could receive 4-valent HPV vaccine (HPV4) to prevent penis cancer, oral cancer, oropharyngeal cancer and anal cancer related to HPV 16 and 18, and genital warts and recurrent respiratory papillomatosis related to HPV 6 and 11. Theoretically, HPV4 vaccination on boys is expected to have a preventive effect on their future sex partners against cervical cancer. According to a recent phase III clinical trial conducted over more than 4,000 men aged between 16 and 26, HPV4 reduced the cases of anal cancer, genital warts, and premalignant or dysplastic lesions caused by HPV 6, 11, 16, and 18 [33, 34]. The MFDS expanded the age of HPV4 vaccination subjects to men 26 years of age. Therefore, in Korea, males aged between 9 and 26 can receive HPV4 vaccine to prevent anal cancer, genital warts, and premalignant or dysplastic lesions.

In the U.S., boys aged 11 and 12 are all recommended to receive HPV vaccine; men aged between 13 and 21 are advised to have follow-up vaccination; and men aged between 22 and 26 are advised to consider receiving vaccination [35]. Everyone with immunocompromising conditions, including HIV, and homosexuals are advised to receive HPV4 before the age of 26. However, in Korea, it is challenging to customize vaccination recommendation according to age group because there has not been sufficient research conducting cost-benefit analysis on recommending different vaccination for people of different ages. The studies that proved the HPV vaccine's efficacy in preventing the aforementioned diseases were conducted mostly in male homosexuals, who have a higher risk of diseases caused by HPV infection along with HIV patients. Therefore, Korea should give more consideration to vaccinating homosexual men or those with HIV.

Recently, there have been concerns regarding the safety of the HPV vaccine. However, the World Health Organization (WHO), through the Global Advisory Committee on Vaccine Safety (GACVS), stated twice, on July 2013 and February 2014, that a worldwide, comprehensive analysis of safety information has revealed that there is no safety risk associated with cervical cancer vaccine or HPV vaccine [36, 37]. Moreover, in March 2014, the MFDS stated that supplements for immune enhancement contained in the HPV vaccine have not shown any safety risk, as a response to concerns raised by some researchers from a Japanese institute [38]. Aluminum hydroxide, the cause for the concerns, is an immune enhancement supplement widely used to improve the effectiveness of vaccines against hepatitis, pneumococcus, and tetanus-diphtheria-pertussis. Its safety has been proved. In fact, the U.S. Food and Drug Administration (FDA) has stated that the maximum amount of aluminum an infant can be exposed to cannot influence his or her health [39]. WHO has also made a statement that aluminum contained in vaccines is harmless [40].

Pregnant women have a higher risk of influenza infection and complications compared to the general population. According to a study conducted in 1918 over 1,350 pregnant women with influenza-like illness (ILI), 43% (585 people) developed pneumonia as a complication, of which 52% (302 people) had a miscarriage [41]. The fatality rate of the subjects was 27%, and it was highest among those in the third trimester of pregnancy. During the 1957 influenza pandemic, influenza accounted for 20% of deaths related to pregnancy, and half of the infected women of childbearing age were pregnant [42]. During the 2009 influenza pandemic, pregnant patients were estimated to be 4 times more likely to be hospitalized than the non-pregnant patients, and they had higher a higher risk of fatality from critical illness [43]. 20% of pregnant women who were hospitalized in the intensive care unit died [44]. Moreover, influenza was found to increase the risk of preterm delivery, low birth weight, and stillbirth [45]. From these findings, WHO designated pregnant women as the most prioritized subjects of influenza vaccination and advised pregnant women to receive inactivated influenza vaccine regardless of gestation weeks [46]. Research on the disease burden of influenza in Korea is still insufficient. In the 2009 pandemic, out of the 19,727 women of childbearing age who visited 8 hospitals for ILI, 150 pregnant patients were diagnosed with A (H1N1) pdm09, and none of them were critically ill [47]. However, in a study conducted at a teaching hospital, one fatality was reported out of 5 pregnant women hospitalized for A (H1N1)pdm09 [48]. There is no research in Korea that shows whether influenza infection increases the risk of preterm delivery, low birth weight, and infant stillbirth, and more research is needed.

A study was conducted that evaluated the relationship between influenza vaccination and pregnancy in terms of the safety of the fetus. Influenza vaccination of a pregnant woman was safe and did not increase the risk of preterm delivery or low birth weight. The vaccination did not only protect the vaccinated women but also their newborn infants from influenza [49, 50, 51, 52]. In fact, indirect immunization from the mother is highly beneficial to infants, because infants under 6 months cannot receive influenza vaccination despite the high disease burden.

Therefore, pregnant women and women of childbearing age must have the highest priority for influenza vaccination during an influenza endemic. Pregnant women are advised to receive the vaccination according to the recommended immunization schedule (from October to December) regardless of gestation weeks. However, the rate of influenza vaccination in pregnancy among Korean pregnant women is only 4 to 20.9%, substantially lower than the vaccination rate among the elderly and people with chronic medical conditions [53, 54, 55]. There should be more efforts to raise awareness among pregnant women about the importance of influenza vaccination through public campaigns, education, and free vaccination programs.

The influenza vaccine used in Korea is a trivalent vaccine that contains antigen representing three influenza viruses - A/H3N2, A/H1N1 and B. However, influenza B viruses can be categorized into two lineages according to the type of antigen (B/Victoria and B/Yamagata), and the cross-reactive immunogenicity between the two lineages is insignificant.

Every year, WHO makes recommendations for vaccine compositions for the Northern and Southern Hemisphere, each according to the lineage that is expected to be epidemic for the year. However, in the last decade, there were lineage-level mismatches between vaccines and circulating strains of influenza B viruses in 50% of the cases. In many cases, influenza B viruses from two different lineages circulated at the same time [56]. In the U.S., five out of 10 seasons from 2001 to 2011 saw lineage-level mismatches between influenza B viruses in vaccines and the circulating B strains. Similarly in Europe, there were mismatches between influenza B vaccines and circulating B viruses in four out of eight seasons from 2003 to 2011. Moreover, 58% of separated viruses belonged to a lineage different from vaccine viruses [56]. According to data provided by the Korea Centers for Disease Control (KCDC), Korea has been seeing influenza B viruses of two different lineages in the same season after the 2009 flu pandemic [57, 58, 59]. The lineage-level mismatch and simultaneous circulation of influenza B viruses are considered as one of the most important factors that undermine the effectiveness of influenza vaccines. WHO, starting from the 2013-2014 season, recommends quadrivalent influenza vaccine, which contains influenza B virus strains of two different lineages [60].

According to clinical trials conducted for approval of quadrivalent influenza vaccine, the vaccine has shown non-inferior immunogenicity and no difference in terms of local or systemic adverse reactions compared to trivalent vaccine [61, 62]. Also, in a large-scale clinical trial conducted on 5,168 children aged between 3 and 8 years to test the efficacy of quadrivalent vaccine, it prevented 59.3% of influenza and was highly effective in preventing moderate or severe influenza infection (74.2%) [63].

After 2012, four kinds of egg-based quadrivalent influenza vaccines have been developed and approved by the U.S. FDA [56]. Of the four vaccines, there are three inactivated influenza vaccines: Fluarix®Quadrivalent, GlaxoSmithKline; Fluzone®Quadrivalent, Sanofi Pasteur; and FluLaval®Quadrivalent, ID Biomedical Corporation/GlaxoSmithKline. FluMist®Quadrivalent, MedImmune, is a live-attenuated influenza vaccine. Korea is repeatedly experiencing influenza B epidemics in March and April with mismatching lineages of vaccines and circulating virus strains, which calls for the introduction of quadrivalent vaccines. Quadrivalent influenza vaccines have been developed in Korea and are undergoing clinical trials. Further studies should be conducted to assess the disease burden of the influenza B virus on children and adults and the cost-effectiveness of quadrivalent vaccines.